The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4385-4389
Copyright © 1999 by The Endocrine Society
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.
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Introduction
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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.
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Transsphenoidal Surgery
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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.
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Pathology
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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 1
. 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.
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.
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Clinical Presentation
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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 2). 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. 1).
GH-releasing tumors have a fairly even distribution among the various
age groups.
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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.
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Corticotrophic Adenomas (Cushing’s Disease)
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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.
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Prolactin-Secreting (Lactotrophic) Adenomas
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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.
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GH (Somatotrophic) Adenomas
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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.
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Endocrine-Inactive Adenomas
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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.
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Incidental Adenomas
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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 3 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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Conclusion
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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.
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References
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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.
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Mindermann T, Wilson CB. 1995 Pediatric pituitary
adenomas. Neurosurgery. 36:259–268; discussion p. 269.[Medline]
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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]
This article has been cited by other articles:
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J W Ironside
Best Practice No 172: Pituitary gland pathology
J. Clin. Pathol.,
August 1, 2003;
56(8):
561 - 568.
[Abstract]
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R. M. Scott and E. T. Hedley-Whyte
Case 35-2002 - A Nine-Year-Old Girl with Cold Intolerance, Visual-Field Defects, and a Suprasellar Tumor
N. Engl. J. Med.,
November 14, 2002;
347(20):
1604 - 1611.
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Introduction
Transsphenoidal Surgery