The tissue effects of chronic
hypercortisolism that result in Cushing's syndrome may be caused by
adrenal tumors, ectopic secretion of adrenocorticotropic hormone (ACTH)
or corticotropin releasing hormone (CRH), severe depression, exogenous
administration of glucocorticoids, or pituitary hypersecretion of ACTH.
Pituitary-dependent hypersecretion of ACTH results in two clinical
conditions that are of particular interest to the neurosurgeon -
Cushing's disease and Nelson's syndrome. Cushing's disease is the
hypersecretion of ACTH by a pituitary source, usually a pituitary
adenoma, that causes bilateral adrenal cortical hyperplasia and
consequent hypercortisolism. Nelson's syndrome, which some patients
develop after undergoing adrenalectomy for the treatment of Cushing's
disease, is the hypersecretion of ACTH by a pituitary adenoma that
results in cutaneous hyperpigmentation. Nelson's syndrome differs from
Cushing's disease in that the hypercortisolism cannot occur because of
the adrenalectomy and, by definition, a pituitary tumour is known to be
present.
Historical Perspective
In 1932, Cushing reported his detailed
study of 12 patients who manifested signs of hypercortisolism during
their lifetime. On the basis of the demonstration of pituitary
basophilic adenomas in six of the eight patients studied at autopsy,
Cushing suggested that there was a causal relationship between the
pituitary tumour and the characteristic bilateral adrenocortical
hyperplasia. A year later, Howard Naffziger performed the first
craniotomy for removal of a pituitary adenoma in a patient with
Cushing's disease. The resection produced a dramatic resolution of
symptoms, but despite postoperative pituitary irradiation, the patient's
disease recurred and she died seven years after the operation. The
convincing implication of a link between pituitary adenoma and
hypercortisolism provided by this case and subsequent case studies did
not dispel scepticism that a pituitary adenoma was the primary defect in
Cushing's syndrome. These doubts were based on the high incidence (10 to
20 percent) of asymptomatic basophilic pituitary adenomas found at
autopsy and on the inability to distinguish biochemically between the
different causes of hypercortisolism. In addition, the available
radiologic techniques were not sensitive enough to detect small
pituitary tumors. Many investigators believed that the primary defect
lay in the adrenal glands. After the introduction of cortisone in 1950,
adrenalectomy became the preferred mode of therapy for all cases of
Cushing's syndrome.
The efficacy of pituitary irradiation in
some cases of hypercortisolism, the lack of consistent pathologic
findings among patients who underwent adrenalectomy, and the recognition
of Nelson's syndrome fostered renewed interest in the concept of a
pituitary origin. These observations supported the notion that at least
two types of Cushing's syndrome exist, one of adrenal origin and one of
pituitary origin. Clayton, in 1958, may have been the first to provide
direct evidence of pituitary hyperfunction in Cushing's syndrome by her
report of two patients with elevated plasma ACTH levels who were found
to have pituitary tumors and adrenal hyperplasia. In the same year,
Nelson reported the development of a pituitary tumour, hypersecretion of
ACTH, and cutaneous hyperpigmentation in a patient who had undergone
bilateral adrenalectomy for the treatment of Cushing's syndrome. In that
case, surgical removal of the pituitary adenoma resulted in resolution
of the hyperpigmentation and apparently complete resolution of ACTH
hypersecretion, as reflected in the finding of no detectable ACTH in the
plasma. The subsequent report by Salassa and colleagues substantiated
Nelson's findings and provided radiologic evidence that, in some
patients, a pituitary tumour was present before adrenalectomy. These
authors suggested that approximately 10 percent of patients undergoing
adrenalectomy for Cushing's syndrome would subsequently develop signs of
a pituitary tumour and cutaneous melanosis. Their findings also
emphasized the existence of complex feedback loops between pituitary corticotropes and the adrenal gland.
Subsequent clarification of the different
biochemical factors involved in the development of Cushing's syndrome
has permitted development of therapies specific for the causes of
hypercortisolism in most patients. These endocrinologic methods
and the results obtained with pituitary microsurgery, which can achieve
lasting remission of disease while preserving normal pituitary function
after the selective removal of a corticotropic adenoma, have
firmly established Cushing's disease as a distinct clinico-pathologic
entity.
Pathogenesis
The pathophysiology of Cushing's disease
is as complex as Cushing predicted in summarizing his cases as being
"so many and varied as to baffle analysis." Although the hormonal
mechanisms that produce the observed clinical features are still poorly
understood, it is known that chronic exposure of tissues to excessive
quantities of cortisol, which influences cytoplasmic and nuclear
receptors, results in Cushing's syndrome. At least two-thirds of all
cases of Cushing's syndrome can be ascribed to a pituitary cause and are examples of pituitary Cushing's
syndrome (Cushing's disease). ACTH-secreting nonpituitary neoplasms
that cause secondary hypercortisolism (ectopic Cushing's syndrome) and
the adrenal disorder causing primary hypercortisolism (adrenal
Cushing's syndrome) are responsible for approximately equal proportions
of the majority of remaining cases of spontaneous Cushing's syndrome.
The periodic or continuous oversecretion
of ACTH (corticotropin) by a pituitary source is now recognized as the
hormonal dysfunction underlying Cushing's disease. There is loss of the
normal diurnal secretory pattern and reduced sensitivity of the
hypothalamus and normal pituitary to glucocorticoid feedback
suppression. The increased stimulation of the adrenal cortices causes
hyperplasia and secondary hypercortisolism. On occasion the hyperplasia
can be nodular. Plasma ACTH levels usually are normal or modestly
elevated in the presence of a high serum cortisol level. High levels of
serum cortisol cause suppression of ACTH secretion by both normal and
neoplastic corticotropes, which is the basis for the use of
dexamethasone suppression tests in the diagnostic differentiation of
Cushing's disease from other causes of Cushing's syndrome. Perhaps in
synergy with the overproduction of ACTH, the adrenal glands are also
more sensitive to stimulation by ACTH.
Hypercortisolism is associated with
increased intravascular. intercellular, and intracellular volume, which
possibly is related to increased mineralocorticoid effects. In addition
to abnormalities in volume, normal plasma renin levels and enhanced
vascular reactivity probably contribute to the hypertension that is
present in up to 75 percent of patients. The increased mineralocorticoid
effects may lead to hypokalemic alkalosis. The glucose intolerance often
observed may be due to partial blockade of insulin receptors by excess
cortisol, and an increase in gluconeogenesis and glycolysis.
Hypercortisolism may also induce a central hypothyroidism.
Hyperlipidemia and hypertension seem to contribute to the accelerated
atherosclerosis and cardiac disease seen in Cushing's disease.
Among patients with Cushing's disease, as
many as 80 percent have a pituitary adenoma. Other pituitary lesions
reported in association with the disease include diffuse or multinodular hyperplasia of corticotropes; multiple, separate pituitary
adenomas; coexisting corticotrope hyperplasia and adenoma; and
gangliocytoma and adenoma. In some cases, total
hypophysectomy has resulted in remission of disease, and serial sections
through the excised gland have revealed no abnormality. These variations
in the pathology of the pituitary, along with clinical data suggesting
that certain neurotransmitters may influence the course of the disease,
have been considered evidence that hypothalamic dysfunction is a factor
in some cases of Cushing's disease. Additional support for
the role of hypothalamic dysfunction may be found in those cases that
respond to medications, such as bromocriptine, somatostatin, and
sodium valproate, that inhibit the secretion of CRH; in examples of
cyclical Cushing's disease; and in patients with psychiatric disorders
that present with a Cushing's disease-like syndrome. In addition, the
rare occurrence of pituitary adenoma mixed with intrasellar gangliocytoma does suggest that neuronal dysfunction may be involved in
the development of some adenomas. However, the failure of pituitary
stalk sectioning to prevent ACTH hypersecretion or to induce remission
of Cushing's disease seems to contradict the theory of a hypothalamic
cause in some cases of Cushing's disease. Furthermore, the return
of normal pituitary function after a prolonged period of hypocortisolism following selective removal of a pituitary
microadenoma implies that the hypothalamus and normal pituitary corticotropes were chronically suppressed rather than hyperactive in
the CRH or inhibitory factors have a role in
the pathophysiology of Cushing's disease or Nelson's syndrome is not
conclusive. Nonetheless, excess CRH, and thus Cushing's disease, could
result from a hypothalamic disorder or an ectopic neoplastic source.
Despite the ongoing debate about the role of the hypothalamus in the
pathogenesis of Cushing's disease, pituitary tumors are considered its
main cause.
In Nelson's syndrome, the loss of partial
cortisol inhibition as a consequence of the adrenalectomy allows the
pituitary tumour to secrete tremendous amounts of ACTH and may also
promote growth of the adenoma. The resulting high plasma levels of ACTH
and other factors stimulate cutaneous melanocytes to produce the
hyperpigmentation characteristic of this condition;
β-lipotropin
(βLPH) and melanocyte-stimulating hormone have not been convincingly
shown to contribute to the hyperpigmentation. In contrast to Cushing's
disease, the tumors of Nelson's syndrome usually do not show
suppression of ACTH secretion in response to the administration of
high-dose dexamethasone. This difference is presumably a consequence of
prolonged "inadequate" cortisol stimulation (suppression of corticotropes) after the adrenalectomy.
The corticotropic pituitary adenomas
responsible for the hypersecretion of ACTH are most often microadenomas
averaging 5 mm in diameter. In Nelson's syndrome more often than in
Cushing's disease (approximately 50 percent compared to less than 20
percent of cases, respectively), the responsible tumour is a
macroadenoma, occasionally one with invasive tendencies. The typical
corticotropic adenoma can be recognized intraoperatively as soft,
sometimes semiliquid, white-to-reddish tissue that is distinct from the
more firm, yellowish normal anterior lobe. However. the adenoma may be
difficult to distinguish from the posterior lobe. Although it has been
suggested that corticotropic adenomas have a predilection for the
central mucoid core of the anterior lobe, they may be located anywhere in the
sella. Lamberts and colleagues have suggested that corticotropic
adenomas originate in either the anterior or the intermediate lobe.
They postulated that tumors originating within the intermediate lobe
contain interspersed axons, are sensitive to a dopamine agonist, have a
greater tendency toward recurrence after surgery, and are an expression
of hypothalamic dysfunction. The retrospective thorough evaluation of 15
cases by Raffel and colleagues failed to reveal axons in any of the
tumors studied. Other reports of patients with bromocriptine-responsive
Cushing's disease have also raised doubt regarding an intermediate lobe
origin.
Microscopically, corticotropic tumors are
composed of compact sheets of uniform polygonal cells having round to
oval nuclei with prominent nucleoli. Often there is a radial arrangement
of tumour cells around capillaries. The surrounding gland and acini are
compressed or destroyed, and the tumour may or may not be well
circumscribed. There are usually no mitoses or other signs of
malignancy, but local invasiveness, subarachnoid dissemination, and
distant metastasis occur more frequently with corticotropic tumors than
with any other pituitary adenoma. although they are still quite rare.
When examined with routine histologic techniques, the tumour cells may
exhibit the classic basophilic staining reported by Cushing. These
densely granulated cells stain positively with periodic acid Schiff
(PAS) stain and lead hematoxylin and usually are indistinguishable from
normal corticotropes. The long-standing classification of pituitary
tumors as chromophobic, basophilic, or eosinophilic is known to be
inadequate, in that these designations have no correlation with the in
vivo secretory product, activity, or cellular origin of the lesion. A
review of Cushing's original report and subsequent experience
indicates that the tumors may also be chromophobic, mixed, or
eosinophilic. Variations in the histologic appearance of the cells
may be a result of minor differences in staining technique, but
they may in some cases relate to the volume of secretory granules
within the tumour cells. Tumors are now classified according to the
secretory product or the cell of origin (e.g., lactotrope,
somatotrope, corticotrope).
Ultrastructural and
immunohistochemical studies of corticotropic adenomas reliably
reveal distinct identifying features. Characteristically, there are
spherical or slightly irregular densecored secretory granules that
average 450 nm in diameter and tend to line up along cell membranes.
These granules stain selectively when anti-ACTH and anti-,β-lipotropin
immunohistochemical techniques are used. Also characteristic is the
presence of bundles of microfilaments, 7 nm in diameter, arranged in
a perinuclear distribution. Robert and colleagues believe that
these perinuclear microfilaments represent the ultrastructural
basis for Crooke's hyaline change. When examined by light
microscopy, Crooke's hyaline change is seen only in non adenoma corticotropes, and only when hypercortisolism is present. The
microfilaments are found in minimal numbers in the tumour and normal
corticotropes of Nelson's syndrome, presumably because there is no
hypercortisolism to induce their deposition. Secretory granules may
be slightly smaller (approximately 200 nm) and ribosomes more
prominent, but otherwise there are minimal ultrastructural
differences between normal corticotropes and the adenoma
corticotropes of Nelson's syndrome. Reuss and colleagues have,
however, been able to find subtle ultrastructural differences
between well-differentiated and undifferentiated ACTH-secreting
adenomas in Cushing's disease and Nelson's syndrome.
Even though there are no
well-established criteria for the diagnosis of corticotrope
hyperplasia, it is claimed that this condition accounts for as many
as 25 percent of cases of Cushing's disease in some series.
These reports contrast markedly with other series in which there
have been no instances of corticotrope hyperplasia. In Wilson's
series of 216 patients treated with microsurgery for Cushing's
disease, only two cases of diffuse hyperplasia were identified, both
of which responded to selective surgery. Definitive criteria for
the recognition of this entity have been proposed by McKeever and
colleagues in their report of a case of Cushing's disease resulting
from multinodular corticotrope hyperplasia. In general, one
expects to find an increase in ACTH-laden corticotropes
interspersed among fewer than 10 percent of non corticotrope
secretory cells, and no evidence of compressed or destroyed acini.
Expanded acini may be seen if the process is focal. Light microscopy
should show no evidence of Crooke's hyaline change in the areas of
suspected hyperplasia.
Clinical Features
Cushing's disease is a serious
endocrinopathy, the natural course of which is unpredictable.
Occasionally Cushing's disease resolves spontaneously, but
resolution can be followed by relapse months or years later.
In some cases, expression of Cushing's disease is cyclical. Of
the hypersecretory pituitary disorders, Cushing's disease has the
highest incidence of morbidity and of persistence after therapeutic
intervention. Untreated, the fully active disease has been
associated with a 5-year survival rate of less than 50 percent.
Death most often results from cardiovascular or infectious
complications. Women constitute over 75 percent of patients with
Cushing's disease; in contrast, there is a predominance of children
(65 percent) in cases of adrenal Cushing's syndrome and of men (60
percent) in cases of ectopic Cushing's syndrome. Most patients with Cushing's disease are between 30
and 40 years old at the time of diagnosis.
No one clinical feature is diagnostic
of Cushing's disease, and the clinical presentation is diagnostic in
less than 50 percent of cases. The classic findings are moon facies,
centripetal obesity, buffalo hump, hypertension, thin skin, purple
abdominal striae, and ecchymoses. Frequently the patients have
emotional disorders, most often depression and psychosis, as well as
menstrual irregularities or impotence, osteoporotic back pain, and
symptoms referable to glucose intolerance. Patients may also have
osteoporosis, proximal muscle weakness, decreased collagen
formation, hypercholesterolemia, and impaired immune function.
Occasionally, patients present with hypokalemic alkalosis and kidney
stones. Patients with a variety of psychiatric disorders (e.g.,
depression, anorexia nervosa, and chronic anxiety), drug dependence,
or glucocorticoid resistance may present with symptoms and signs
that mimic Cushing's disease. The prominent supraclavicular and
mandibular fat pads seen in cases of Cushing's disease are not
present in the "pseudocushingoid" patient with exogenous obesity who
occasionally presents with complaints and laboratory findings
suggestive of Cushing's disease.
Other hormones probably contribute
primarily or secondarily to the clinical syndrome For example,
plasma testosterone, presumably from the adrenals, is significantly
elevated in females who have Cushing's disease and may contribute to hirsutism, acne, and mental disorders. In contrast, testosterone is
usually reduced to less than one-third normal in males, which may be
the cause of oligospermia and impotence. Growth hormone secretion
during sleep and in response to provocative stimuli such as growth
hormone releasing hormone is significantly blunted in patients with
Cushing's disease. The secretion of other pituitary hormones, such
as prolactin and thyroid stimulating hormone, is often abnormal in
Cushing's disease, and the hypersecretion seems unrelated to the
mass effect in those cases with an adenoma. The role of galanin,
which may influence the secretion of other pituitary hormones and
is mainly found in corticotropes, is being investigated. A
clear hormonal basis for the hypertension is yet to be demonstrated.
In many cases, hypertension, mental illness, and obesity persist
despite adrenalectomy.
In comparison with the symptoms of
endogenous Cushing's disease, only obesity, acne, and mental
symptoms (typically hyperactivity and elation) occur as frequently
in patients who are given high-dose glucocorticoids (exogenous
Cushing's syndrome) as part of a therapeutic regimen for unrelated
disease. In this same group, less than 29 percent of patients
develop hypertension, and hyperpigmentation does not occur at all. A
similarly low incidence of hypertension is noted in patients with
ectopic Cushing's syndrome, despite the fact that they have the
highest levels of ACTH and cortisol observed in any of the groups.
However, in 25 percent of cases of ectopic Cushing's syndrome,
cutaneous hyperpigmentation occurs.
Nelson's syndrome appears
unpredictably months to years after adrenalectomy; its incidence is
highest in patients who underwent adrenalectomy during childhood. so
Nelson's syndrome seems to occur as frequently in men as in women,
but its incidence may be less among patients who receive pituitary
irradiation after their adrenalectomy. The incidence of Nelson's
syndrome is also significantly reduced if autotransplantation of
adrenal tissue is performed at the time of bilateral
adrenalectomy. A history of Cushing's syndrome that has been
treated by adrenalectomy in a patient who complains of increased
cutaneous pigmentation and has an enlarged sella turcica is
diagnostic of Nelson's syndrome. Compared to patients with
Cushing's disease, who have a very low incidence of headaches or visual
symptoms, those with Nelson's syndrome are more likely to have
headaches or visual system impairment as a consequence of a mass
effect or tumour invasion. A significant proportion of patients with
Nelson's syndrome have died from the direct effects of their
tumors.
Diagnostic Evaluation
The diagnosis of Cushing's disease is
established by endocrinologic criteria. If doubt regarding the
cause persists, or if microsurgical exploration of the pituitary is
unrewarding and total hypophysectomy is contraindicated, selective
venous sampling for ACTH should be performed. Plasma ACTH
levels in samples from either the cavernous or the inferior
petrosal sinus, the jugular bulb, the thyroidal veins, and the
superior and inferior vena cava are compared with a peripheral
venous sample obtained simultaneously. An inferior petrosal sinus
to peripheral ACTH ratio of more than 2: I is generally a reliable
indicator of Cushing's disease and may support a recommendation of
partial or total hypophysectomy for a patient in whom a negative
pituitary exploration has been performed. Because of variations in
the venous drainage of the pituitary and cavernous sinuses,
bilateral petrosal sampling should be performed, but it should not
be relied on to indicate lateralization of the tumour when positive.
Yanovski and colleagues also caution against the use of petrosal
sinus sampling to distinguish between patients with mild Cushing's
disease and pseudo-Cushing's states.
In the past, the radiologic
evaluation of the sella employed hypocycloidal poly tomography and
high-resolution computed tomography (CT) scanning with sagittal and
coronal reformations. These studies can delineate the sella and
localize focal abnormalities. Unfortunately, the high incidence of
incidental bone abnormalities found on poly tomography and of nonspecific changes in pituitary parenchymal attenuation seen on CT
scans emphasize the need to rely on endocrinologic criteria for
diagnosis. In patients subsequently proved to have Cushing's
disease, high-resolution CT scanning may demonstrate an abnormality
consistent with an adenoma in as few as 25 percent and with an
accuracy of approximately 39 percent. Magnetic resonance
imaging with gadolinium enhancement, currently the radiographic
procedure of choice, has a higher sensitivity, approximately 55 to
100 percent, for visualizing adenomas in Cushing's
disease. If endocrinologic criteria are met, radiologic
studies showing no abnormalities should not dissuade the surgeon
from performing a trans-sphenoidal exploration.
Medical Management
For the patient with Cushing's
disease or Nelson's syndrome who is not considered a candidate for
surgical intervention or who has an unresectable or incompletely
treated tumour, medical therapy may be an option. Medical therapy
is only palliative, however, and should be reserved for use in
preparation for surgery, in conjunction with pituitary irradiation,
or after both these modalities have failed to achieve a cure. Drug
therapy is directed at reducing the secretion of ACTH by the
pituitary or at interrupting adrenal steroidogenesis.
Cyproheptadine, a serotonin
antagonist, and bromocriptine, a dopaminergic agonist, are thought
to alter hypothalamic neurotransmitters that regulate CRH. It is
also possible that cyproheptadine exerts direct effects on pituitary
corticotropes. Cyproheptadine reportedly has achieved
remission in more than 50 percent of patients with Cushing's
disease. A dosage of 24 mg/day is attained gradually; if it is
effective, chemical and clinical remission should be evident within
2 to 6 months. A relapse while the patient is under treatment, and
the side effects of somnolence and hyperphagia-especially in
children - may limit the usefulness of the drug in some cases. Results
reported with the use of bromocriptine to treat Cushing's disease
have been contradictory. Lamberts and colleagues have
presented evidence that patients whose corticotropic adenomas
originate in the intermediate lobe suppress ACTH secretion in
response to 10 mg per day of bromocriptine. After discontinuation of
cyproheptadine or bromocriptine therapy, a relapse can be expected
in virtually all cases. The recent finding that naloxone,
somatostatin analogues, sodium valproate, and reserpine may
selectively suppress corticotropin hypersecretion in patients with
Cushing's disease, Nelson's syndrome, or Addison's disease may
indicate other avenues for improved medical therapy in the future.
Ketoconazole, aminoglutethimide,
metyrapone, o.p'-dichlorodiphenyldichloroethane (o.p'-DDD), and
trilostane have been used effectively to direct pharmacologic
therapy to the adrenal cortices. These adrenoactive agents do not
suppress either the secretion of ACTH or the growth of the pituitary
lesion. ACTH levels in plasma may increase during effective anti
adrenal therapy in a manner analogous to the increase of ACTH
levels in patients with Addison's disease or during the development
of Nelson's syndrome. Although o.p'-DDD is toxic to the adrenal
cortices, it has been used at a reduced dosage to block
steroidogenesis chronically. Its side effects include sedation,
depression, gastrointestinal problems, and permanent adrenal damage. Aminoglutethimide, which inhibits the conversion of cholesterol to
pregnenolone, blocks the first step in steroidogenesis. It has been
used successfully alone as well as in combination with metyrapone.
Metyrapone blocks the 11-hydroxylase step in cortisol production,
and can provide long-term control of the hypercortisolism. Hirsutism and hypertension have been a problem with the prolonged
use of metyrapone, and 20 to 30 percent of patients develop skin
rash, hypothyroid goiter, somnolence, dizziness, blurred vision, or
gonadal toxicity while taking aminoglutethimide. Mineralocorticoid
and glucocorticoid replacement is required with the use of o.p'-DDD
or aminoglutethimide. Ketoconazole, an antifungal agent, has been
found to be particularly useful in blocking
hypercortisolism. It inhibits steroidogenesis at several
sites, and generally is well tolerated. Its side effects include
hepatoxicity, gastrointestinal effects, skin rashes, and
gynecomastia in men. The antiprogesterone agent RU 486 may also have
efficacy in the symptomatic treatment of hypercorticolism caused by
Cushing's disease.
Radiation and Surgical Therapy
The goals of definitive therapy
should be (1) to eliminate the inappropriate secretion of ACTH and
hypercortisolism; (2) to eradicate the responsible lesion; and (3)
to prevent permanent dependence on hormone replacement by averting
endocrine deficiency.
As primary therapy, irradiation of
the pituitary gland, either with heavy particles or from a
megavoltage source, produces remission of disease in 50 to 80
percent of patients with Cushing's disease, and in a much smaller
percentage of those with Nelson's syndrome. Children
appear to respond better than adults to this form of therapy. The
efficacy of pituitary irradiation, however, is qualified by the
delay in hormonal response and by the risk of radiation damage to
normal structures included in the treatment fields. In addition,
most patients who undergo radiation therapy subsequently develop
some degree of hypopituitarism. In many cases, pituitary irradiation
is used in addition to medical measures to control hypercortisolism,
Low-dose external pituitary irradiation for the treatment of
Cushing's disease has been found to have relatively poor efficacy.
Selective microsurgical removal of
corticotropic microadenomas has proved to be the most effective way
to achieve the goals of definitive
therapy. The refinement of
transsphenoidal pituitary microsurgery constitutes the single most
important advance contributing to the successful treatment of
Cushing's disease and Nelson's syndrome. When performed by an
experienced surgeon, this procedure has a very low incidence of
morbidity and mortality.
The microadenomas are rarely located
on the surface of the anterior lobe, and often must be exposed by a
systematic, thorough dissection through an apparently normal
gland. In exceedingly rare instances, a microadenoma is
found outside the pituitary gland. For consenting adults, total
hypophysectomy should be considered an option if no abnormality is
demonstrated at the time of operation, as an undetectably minute
adenoma may be presumed to be the source of disease. Craniotomy
should be restricted to those cases in which parasellar extension of
tumour or a small sella turcica precludes adequate access to a large
suprasellar tumour by the transsphenoidal route. Adrenalectomy
should be used only as a last resort, after pharmacologic therapy,
pituitary surgery, and irradiation have failed to produce a cure.
The results of transsphenoidal
microsurgical management of ACTH-secreting pituitary tumors derived
from large representative reports in the literature indicate that
the rate of remission obtained by selective removal of a
microadenoma can be greater than 90 percent. Extrasellar extension
of tumour, macroadenomas, the failure to demonstrate tumour, the
presence of Nelson's syndrome, or any combination of these, is
associated with a poorer outcome. In addition, there are
still cases in which an ectopic cause of Cushing's syndrome
masquerades as Cushing's disease, and results in a failure to
respond to pituitary microsurgery. In each series, long-term
remission. of disease was associated with a prolonged (more than 3
months) period of hypocortisolism after successful microsurgery;
during this period, steroid replacement was required for at least 6
months. Hypopituitarism occurred only in those patients in whom
hypophysectomy was performed intentionally. Among patients
initially considered cured, approximately 5 to 10 percent will have
tumour recurrence. Overall long-term follow-up suggests that 64 to 83
percent of patients can be cured with transsphenoidal microsurgery.
In contrast, less than 30 percent of
patients with Nelson's syndrome who undergo surgery can be expected
to have remission of disease, regardless of tumour size. The high
incidence of cranial nerve dysfunction, the tendency toward invasion
of surrounding structures by tumour, and the poor response to all
treatment modalities associated with Nelson's syndrome emphasize
that adrenalectomy should be used to treat Cushing's disease only
after all other therapy has failed.
The specificity of
transsphenoidal microsurgical exploration of the pituitary gland and the high
likelihood of cure following selective transsphenoidal microsurgery
make this approach the present treatment of choice. It should be the
primary treatment for all patients with Cushing's disease or
Nelson's syndrome.
