Pediatric Pituitary Adenomas

Sandeep Kunwar and Charles B. Wilson

Department of Neurosurgery, University of California–San Francisco, San Francisco, California 94143

Address correspondence and requests for reprints to: Charles B. Wilson, Department of Neurosurgery, University of California–San Francisco, 505 Parnassus Ave, Box 0112, San Francisco, California 94143.


    Introduction
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
OVER THE PAST 29 years, the junior author (CBW) has performed 150 transsphenoidal operations on children and adolescents for pituitary adenomas, and this experience provides insights into the development and presentation of pituitary adenomas in the pediatric population. In preparing this review, rather than following the standard journalistic format, we took a personal perspective on surgical management that should be more helpful to endocrinologists and pediatricians in detecting pediatric pituitary adenomas and making decisions about the treatment of patients for whom surgery is a consideration.


    Transsphenoidal Surgery
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Transsphenoidal surgery has become an operation with remarkably little morbidity and near zero mortality. Recovery is rapid, with most patients leaving the hospital on the following day and returning to most regular activities in 1–2 weeks, a dramatic contrast to the morbidity and mortality of treating adenomas by a craniotomy in the past. Complications, minor and major, occur infrequently in the most experienced hands. A subtle loss in pituitary function can be a serious concern in a patient of any age, but especially in children and young adults. Considering the benign behavior of pituitary adenomas, the preservation and possible improvement of anterior pituitary function assumes an equal priority to that of avoiding injury to critical parasellar structures.

We subscribe to the principle of specialized care, and if it makes sense for interested internists and pediatricians to acquire special knowledge and experience in endocrinology, it seems reasonable to apply the same rationale to specialization in pituitary surgery. Particularly in neurosurgery practice makes perfect, and concentrating, rather than diffusing, surgical referrals by encouraging one of several neurosurgeons in larger communities to become the local expert in pituitary surgery can provide improved outcomes for your patients. Care of high quality is rarely cost-ineffective in children, and particularly in pediatric patients with Cushing’s disease, in which inexpert pituitary surgery can be very expensive, financially and in quality of life, in both the short-term and the long-term. Specialists in endocrinology have a critical role in the diagnosis, preoperative preparation, and postoperative management of all pediatric patients with pituitary adenomas. The short- and long-term follow-up of pediatric patients treated by surgery is best placed in the hands of an endocrinologist because critical decisions regarding recurrence of endocrine-active adenomas and the subtleties of anterior pituitary insufficiency require continuous monitoring by an expert for optimal outcomes.


    Pathology
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Immunostaining on all pituitary adenomas is done routinely at the University of California–San Francisco (UCSF), even though it provides critically important information in only a minority of cases. Such practice allows detection of nodular corticotrophic hyperplasia or determination of PRL production by an adenoma vs. nonspecific effect from the compression and distortion of dopaminergic vascular pathways. This careful analysis provides accurate data on the exact cell-type of adenoma, which in turn dictates management and follow-up.

The distribution of tumor cell types in the pediatric adenomas treated by CBW at UCSF is listed in Table 1Go. For several reasons, the distribution of cell types does not reflect the true overall proportion of cell types of pediatric pituitary adenomas. Because this is a series of tumors removed surgically, it does not recognize asymptomatic adenomas, or PRL-secreting adenomas that are managed satisfactorily by medical means and, therefore, not referred for surgery. Furthermore, because of an institutional interest in Cushing’s disease, the proportion of ACTH-secreting adenomas in the series may be misleadingly high.


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Table 1. Occurrence of pediatric pituitary adenomas by age group

 
The most common type of pituitary adenoma was the prolactinoma, followed by ACTH-releasing adenoma causing Cushing’s disease. In the pediatric population, endocrine-inactive adenomas are rare, whereas they comprise 30% of adenomas in adults. These tumors were recognized from symptoms of local mass effect, and although immunostaining revealed that many tumors contained one or several pituitary cell types, a secretory syndrome was not associated with the mass effect.


    Clinical Presentation
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Pituitary adenomas in this population have characteristic clinical presentations as a result of pituitary hormone hypersecretion and/or disruption of growth regulation and sexual maturation (Table 2Go). Pituitary hormone hyposecretion almost always begins with GH, followed by gonadotropins and later by thyroid-stimulating hormone. Growth retardation and short stature are common presentations of all adenomas, except for GH-releasing tumors. This predictable sequence of secretory failure reflects the vulnerability of GH-releasing cells to local compression. In the case of ACTH-secreting adenomas, growth retardation or arrest is the direct effect of hypercortisolemia on the developing skeletal system. Menstrual irregularity or amenorrhea is a common symptom of most adenomas in adolescent girls. Visual field impairment is less common than in the adult population because nonsecreting macroadenomas in this age group are infrequent. Particular to this patient population is the frequency of hormone-secreting adenomas and their distribution within prepubescent (0–11 yr), pubescent (12–17 yr), and postpubescent (18–19 yr) age groups, the latter mimicking the adult population. ACTH-releasing adenomas dominate the youngest group and then decrease in frequency with advancing age and a concurrent increase in the incidence of prolactinomas (Fig. 1Go). GH-releasing tumors have a fairly even distribution among the various age groups.


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Table 2. Clinical findings and tumor characteristics in pediatric adenomas

 


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Figure 1. Frequency of pituitary adenomas by age. The percentages in each age group add up to 100. The different adenoma types are listed in the same order for each age group.

 

    Corticotrophic Adenomas (Cushing’s Disease)
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Children and adolescents present with symptoms and clinical courses somewhat different from those seen in adults. ACTH-releasing adenoma is the most common adenoma in prepubescent children and then decreases in frequency in pubescent and postpubescent children. Patients most commonly present with weight gain that tends to be generalized rather than centripetal. The most sensitive indicator of excess glucocorticoid secretion in children is growth failure, with most patients 1–2 SD below the mean for their age. We have also found psychological changes in our patients, primarily with compulsive behavior and overachievement in school in contrast to the typical adult psychological disturbances of emotional liability, decreased concentration, and depression. Adenomas causing Cushing’s disease are significantly smaller than all other types of adenomas at presentation. Before surgical evaluation most patients have undergone preoperative diagnostic studies, including 24-h urinary excretion of cortisol and 17-OHCS and dexamethasone suppression testing. As in adults, there was an absent diurnal rhythm of plasma cortisol and ACTH and an increase urinary excretion of 17OHCS in almost all patients.

All patients should undergo magnetic resonance imaging (MRI) with the administration of gadolinium. Our previous review shows this imaging modality had a 72% sensitivity in localizing the adenoma (1). However, their small size and the likelihood of a false positive MRI in 15% of the normal population argues for preoperative venous sinus sampling in selected cases. Bilateral venous sampling is technically difficult in children, and the risk of morbidity from the procedure or anesthesia is not entirely insignificant. Therefore, we recommend such exploration occur at centers with wide experience because interpretation of such a study can also be difficult. If a patient with no anomalous venous drainage patterns exhibits a lateralizing ACTH gradient of 2:1 or greater, then removal of the appropriate half of the anterior pituitary gland will be curative in 80% of cases. In the presence of a negative surgical exploration, a guide to the probable location of the adenoma is invaluable. Under the right circumstances, a hemihypophysectomy is appropriate and, in most cases, will be successful. Clinical observations support the view that one third, or even slightly less, of a normal anterior pituitary gland can provide normal anterior pituitary function.

Treatment of Cushing’s disease is transsphenoidal adenomectomy. The surgical exploration must be meticulous and must include the posterior lobe. The corticotrophic adenoma has distinctive gross characteristics. It is dirty-white and soft, bordering on semiliquid, and is often freckled by petechial hemorrhage. The adenoma often has a diameter of 2 mm or less. It can reach the surface of the anterior lobe, can be exophytic into the subarachnoid space, can invade or even lie entirely within the cavernous sinus or its wall (3), and, rarely, it can originate in the posterior lobe. Exploration of the pituitary gland begins on the side with the radiographic abnormality or the side of the ACTH gradient on venous sampling. If no tumor is found, a second exploration of the "abnormal" side is performed and then careful exploration of the opposite "normal" side is performed. Several patients have been operated on after a hemihypophysectomy was performed elsewhere based on an assumed infallibility of inferior petrosal venous sampling: at a second operation, the microadenoma was removed from the unexplored "normal" remaining anterior lobe. Hemihypophysectomy is indicated after a negative exploration (i.e. in a child who has a clearly lateralized venous gradient with a normal venous anatomy and with informed parental consent), at which time the stalk must not be injured. Radiation therapy is suboptimal in the pediatric population because of the risks of injuring pituitary function and because its effects in correcting hypercortisolemia are delayed and uncertain.

Cushing’s disease is a rare disease that, if left untreated, is fatal. With no other tumor is the surgeon’s experience more critical in determining outcome, and for this reason inexperienced pituitary surgeons must gain experience with less complex tumor types, initially referring pediatric patients with Cushing’s disease to an experienced colleague.


    Prolactin-Secreting (Lactotrophic) Adenomas
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Prolactinomas are the most common type of adenoma in children older than 12 and are most common in girls. These tumors present with primary amenorhea in females and with gynecomastia and hypogonadism in males. The prolactinoma is the only pituitary adenoma for which medical management in the long-term is fully satisfactory, and for that reason the proportion of patients with prolactinomas referred for surgical consultation varies widely in different geographic regions. In many parts of the country, surgeons are referred only those patients who have unacceptable side effects caused by medication, patients with dopamine agonist-insensitive adenomas, and those patients who after becoming informed, for personal reasons, select surgical over medical management. In our referral area, the pattern of management is reversed with surgical management being selected initially, particularly for surgically curable micro- adenomas.

Based on the basal prolactin level and a high-resolution MRI of the sella, one can make a prediction for the likelihood of surgical cure. If cure is not possible because of extrasellar spread, particularly cavernous sinus invasion, surgery is not advised unless the patient fails to respond to medical management. From our experience, extension into the cavernous sinus is overestimated based on the MRI alone because macroadenomas can push the wall of the cavernous sinus laterally, giving the appearance of invasion. When there is no chance of surgical cure, the objective of surgery is to reduce the adenoma’s mass, in order to reduce the production of PRL to a level that can be further reduced into a desirable range by a tolerated dose of a dopamine agonist or to relieve symptoms of compression and reduce the bulk of the adenoma before irradiation. Even after radiation therapy, prolactinomas continue to secrete PRL for several years and, therefore irradiation is a poor and very delayed means of treating the hyperprolactinemic syndrome.

In general, the level of PRL in the blood corresponds to the tumor size, such that hyperprolactinemia from a large adenoma with a mildly elevated PRL reflects stalk compression. The postoperative PRL value, obtained 1–2 days after surgery, provides an accurate prediction of outcome: an unmeasurable (<2 ug/L) value predicts a cure with more than 90% probability, and higher values within the normal range indicate incomplete removal of the adenoma. Surgery of prolactinomas, even in the pediatric population, has good outcome with long-term surgical cure of 82% for all prolactinomas (median follow-up, 5 yr) (2), with very low morbidity and no mortality.

Dopamine agonists, such as Parlodel, inhibit tumor-cell replication in the majority of prolactinomas and can result in normalization of PRL levels in these patients. Despite a dramatic reduction in tumor size in the majority of patients treated with dopamine agonists, elimination of the tumor has not been reported, and, subsequently, these patients will require life-long pharmacological treatment. For patients with residual or recurrent adenoma after surgery, often a small dose of Parlodel, taken at bedtime, is sufficient to maintain or restore normal PRL levels and prevent tumor regrowth. Irradiation is reserved for those few patients with surgically unresectable disease who are intolerant of medications. The risk of developing or aggravating pituitary insufficiency remains a major drawback to parasellar radiotherapy.


    GH (Somatotrophic) Adenomas
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
GH-releasing adenomas account for about 10% of surgically treated pituitary adenomas in patients younger than 20 yr of age. Not surprising, rapid growth and acromegalic features are the most prominent symptoms, and in girls menstrual irregularities are common. Occasionally, GH-releasing adenomas can cause precocious puberty and weight gain. The preferred primary treatment for the patient with acromegaly remains surgery with surgical cure at 83% (2). As a general rule, younger patients have larger tumors and higher GH values than older patients. A greater degree of invasiveness correlated with a higher recurrence rate for these tumors. For patients in whom surgical management fails, somatostatin analogs can provide biochemical normalization of GH levels and insulin-like growth factor-I levels in adults, although significant experience in children has not been reported. Conventional radiation therapy prevents tumor progression and can reduce GH hypersecretion in 60–80% of patients, although its effects in normalizing GH levels are delayed several years and it has the risk of injuring normal pituitary function.


    Endocrine-Inactive Adenomas
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
In this category are adenomas that produce no clinically recognizable secretory product. Only 2.7% of our pediatric patients had endocrine-inactive adenomas. It remains unclear why endocrine-inactive adenomas are infrequent in children when they account for almost one third of pituitary adenomas in adults. At the time of diagnosis, these tumors were the largest of the adenomas and, consequently, most patients present with impaired vision and some expression of hypopituitarism, with or without associated headache.

Nearly all symptomatic endocrine-inactive macroadenomas have extended beyond the confines of an expanded sella turcica, the most common pattern of extrasellar growth being directly upward into the suprasellar space. Neither suprasellar extension nor focal perforation of the sellar floor, alone or combined, precludes complete removal. With some exceptions, the only patterns of growth that preclude total removal are lateral extension into the cavernous sinus or middle fossa. Invasion of the dura separating the sella from the cavernous sinus, even without extension into the sinus itself, renders the tumor surgically unresectable unless the invasion is focal, in which case the involved dura can sometimes be removed. A large tumor can displace the intact dural wall of the cavernous sinus far laterally without perforating the dura and mimic extension into the cavernous sinus on MRI.

The surgical objective in treating large endocrine-inactive adenomas is decompression of the optic nerves and chiasm. Unless the tumor invades the cavernous sinus, complete removal of the tumor with preservation of the compressed anterior lobe is possible in the majority of cases, and today’s objective should be curative surgery with preservation of anterior pituitary lobe function. In the majority of large adenomas, a clean surgical plane separates the surface of the tumor from the compressed normal structures. By finding and developing this plane early in the process of tumor removal, a surprisingly large proportion of macroadenomas can be resected completely. Our belief is that more than half of the endocrine-inactive adenomas can be cured by surgery alone, and for this reason the surgeon should go into the operation with complete removal, rather than decompression, as the goal. Loss of preoperative anterior pituitary function has been an infrequent complication; more often, function that was lost preoperatively later returned spontaneously.


    Incidental Adenomas
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
A mass within the sella, whether a cyst or adenoma, can cause compression of the anterior pituitary lobe. Of the anterior pituitary cell types, somatotrophs are the most vulnerable to compression, followed by gonadotrophs as a distant second. Because GH secretion is essential for the normal development of children, short stature is a common sign in many pediatric adenomas. Furthermore, in an asymptomatic patient, if GH secretion is normal, other anterior pituitary functions are most likely to be normal, as well. The presence of calcification, stalk enhancement, or clinical evidence of diabetes insipidus should alert the physician to the presence of either a craniopharyngioma or germ cell tumor. Any incidental adenoma or cyst confined to the sella, discovered in a patient who is asymptomatic and who has normal pituitary function, including GH response to provocative testing, should be left alone. The patient should be advised to have a follow-up examination by a physician who accepts responsibility for periodic clinical, laboratory, and radiographic assessments. Younger patients require more frequent evaluation of their height and sexual development as well as periodic evaluation of the pituitary axis and radiographic imaging because benign adenomas and cysts can expand and cause pituitary compression.

Indications for removal of incidental intrasellar tumors and cysts are individualized according to the patient’s age, sex, development, and the size of the lesion. Table 3Go provides relative indications for surgical intervention. An asymptomatic adenoma that has doubled in size within a year is far more troubling than an adenoma that has shown slight but unquestioned growth over the course of 5 yr. We have included a pure cyst that is larger than 1cm because its potential for further expansion at some unpredictable growth rate is different than the small cysts seen commonly in the pars intermedia. In other words, we are convinced that in this age group, a cyst that has reached a diameter of 1cm is "committed."


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Table 3. Relative indications for surgical intervention

 

    Conclusion
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 
Although rarely fatal because of their unrestrained growth, pediatric pituitary adenomas can have a profound effect on the quality of life and, in many cases, lead to secondary complications caused by endocrine dysfunction that affect not only quality but also length of life. This is especially true in younger children who are in periods of rapid sexual and skeletal development. Early evaluation and intervention, either medical or surgical, is necessary in the child with a pituitary adenoma to avert permanent consequences of pituitary-related endocrinopathy. Technological advances during the past 2 decades have produced more effective therapeutic tools than were available at any time in the past. But even so, optimal management of any pituitary adenoma affecting patients in the most vulnerable of age groups requires particular thoroughness in the evaluation process and the expert application of medical and surgical interventions.

We express particular gratitude to the pediatric endocrinologists at UCSF from whom we have learned so much.

Received September 17, 1999.

Revised October 5, 1999.

Accepted October 5, 1999.


    References
 Top
 Introduction
 Transsphenoidal Surgery
 Pathology
 Clinical Presentation
 Corticotrophic Adenomas...
 Prolactin-Secreting...
 GH (Somatotrophic) Adenomas
 Endocrine-Inactive Adenomas
 Incidental Adenomas
 Conclusion
 References
 

  1. Devoe DJ, Miller WL, Conte FA, et al. 1997 Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing’s disease. J Clin Endocrinol Metab. 82:3196–3202.
  2. Mindermann T, Wilson CB. 1995 Pediatric pituitary adenomas. Neurosurgery. 36:259–268; discussion p. 269.[Medline]
  3. Wilson CB, Mindermann T, Tyrrell JB. 1995 Extrasellar, intracavernous sinus adrenocorticotropin-releasing adenoma causing Cushing’s disease (see comments). J Clin Endocrinol Metab. 80:1774–1777.[Abstract]