Pituitary Tumors: Complex Symptoms and Management
Pituitary tumors, a diverse group of tumors arising
from the pituitary gland, produce such a confusing constellation
of symptoms that diagnosing them can be tricky and managing
them can be challenging. Often overlooked, pituitary
tumors are the third most common tumor of the central
nervous system after gliomas and meningiomas. Nearly
all pituitary tumors are benign and therefore not included
in statistics collected by state cancer registries.
Nonetheless, studies suggest that as many as 14.7 individuals
per 100,000 population are diagnosed with a pituitary
adenoma annually. This overt incidence underestimates
the actual prevalence that, by autopsy series and MRI
evidence from around the globe, reaches a figure as
high as 25% of the population.(i)
Because of its close proximity to the brain, intracranial
nerves and blood vessels, as well as the vital hormonal
control that the gland provides, pituitary tumor symptoms
often mimic a variety of disorders, both hormonal and
neurological.
“The prevalence of pituitary tumor suggests that
physicians need to recognize the complex web of symptoms,”
says Dr. Gail Rosseau, neurosurgeon and member of the
Chicago Institute of Neurosurgery and Neuroresearch.
“It is all too easy to treat the non-specific,
incidental symptoms individually. For example, a patient
who complains of progressive vision loss and loss of
libido is referred to the ophthalmologist for stronger
glasses, and given a prescription for Viagra® to
treat erectile dysfunction. In fact, these are two symptoms
that, considered together, should be red flags that
pituitary disease could be the culprit.”
Dr. Rosseau is among a handful of neurosurgeons in
the country specializing in pituitary tumors, and one
of the few neurosurgeons in Chicago trained and experienced
in transsphenoidal pituitary tumor resection. She says
it is not uncommon for a patient to be referred to several
specialists, including an ophthalmologist, otolaryngologist,
endocrinologist, neurologist and neurosurgeon, prior
to receiving an accurate diagnosis.
“In this multi-referral situation, it is often
the neurosurgeon’s job to quarterback the team,”
Dr. Rousseau says.
The importance of a strong referral cannot be overstated.
Recent studies suggest that higher-volume surgeons and
hospitals provide superior outcomes after transsphenoidal
pituitary tumor surgery. Lengths of stay are shortened,
with a trend toward lower charges. Patients choosing
low-volume neurosurgeons who performed pituitary tumor
resections at low-volume hospitals are more likely to
be discharged to locations other than home. Higher volumes
are also associated with lower rates of complications.
(ii)
CLASSIFICATION
| CLINICAL PRESENTATION(viii)
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Pituitary tumors can be either functional, also known
as secretory because they are hormone-producing; or
nonfunctional, often referred to as non-secretory because
they produce no hormones. Up to seventy-five percent
of pituitary adenomas can produce hormones. They are
categorized by size. Microadenomas are smaller than
1cm and rarely damage the rest of the pituitary or neighboring
tissues. Tumors larger than 1cm are called macroadenomas.
These may cause symptoms either because of the hormones
they secrete, or because they can damage normal pituitary
tissue or nearby nerves, including the optic nerve.(iii)
Prolactinomas
The most common type of secretory pituitary tumor is
prolactinoma (PRL). It represents approximately 40%
of all pituitary adenomas. Prolactinomas can cause symptoms
secondary to the hormonal effects of excess PRL and
to the space-occupying effects of the tumor itself.
Effects vary with the age and sex of the patient and
with the duration and degree of hyperprolactinemia.
Reproductive-aged females can present with infertility
and/or menstrual disturbances, including oligomenorrhea,
amenorrhea, or irregular menstrual cycles. Occasionally,
if prolactinoma occurs in a person of younger age, delayed
menarche can result.
Galactorrhea can be spontaneous or expressive (only
upon squeezing of the nipples). It is observed in up
to 30-80% of these women and can be quite distressing
for the patient. Other features of hypoestrogenism include
vaginal dryness, dyspareunia, and a decline in bone
mineral density (i.e., osteopenia or osteoporosis).
Males with prolactinoma have one or more features of
hypogonadism, which may include decreased libido, erectile
dysfunction, or infertility.
If a prolactinoma develops prepubertally in young males,
hyperprolactinemia may result in a female body habitus
and small testicles. If the prolactinoma is large enough
to compress the surrounding normal hormone-secreting
pituitary cells, it may result in deficiencies in one
or more other hormones (eg, thyroid-stimulating hormone
[TSH], GH, adrenocorticotropic hormone).(iv)
Growth Hormone-Secreting Adenomas
Growth hormone-secreting adenomas represent about 17%
of all pituitary adenomas. Chronic overproduction of
growth hormone (GH) causes acromegaly, the symptoms
of which develop insidiously. Acromegaly can take years,
even decades to become apparent, with a mean duration
of symptom onset to diagnosis of 12 years. The mean
age at diagnosis is 40-45 years. There is no clear relationship
between incidence and race. Symptoms can be divided
into two groups: local mass effects and excessive production
of GH/IGF-I.
Local mass effects of the tumor vary depending on size.
The most common symptoms are headaches and visual field
defects, depending on which part of the optic nerve
pathway is compressed. The most common manifestation
is a bitemporal hemianopsia (partial blindness or “tunnel
vision”) due to pressure on the optic chiasm. Tumor
damage to the pituitary stalk might cause hyperprolactinemia
due to loss of inhibitory regulation of prolactin secretion
by the hypothalamus. Damage to normal pituitary tissue
can cause deficiencies of glucocorticoids, sex steroids,
and thyroid hormone.
Symptoms due to excess of GH/IGF-I are complex and
include soft tissue swelling and enlargement of the
extremities. Patients report an increase in ring and/or
shoe size, as well as a coarsening of facial features.
Macroglossia (tongue enlargement) and prognathism (jaw
protrusion) may also be apparent.(v)
Corticotropin (ACTH)-secreting Adenomas
Corticotropin (ACTH)-secreting adenomas make up about
7% of all pituitary adenomas. The tumor secretes too
much ACTH, causing the otherwise normal adrenal glands
to produce too much cortisol. The result is Cushing’s
disease. Average age of onset is 40 years. Common symptoms
of Cushing’s include truncal body obesity, severe
fatigue and muscle weakness, high blood pressure, backache,
elevated blood sugar, easy bruising, and bluish-red
stretch marks on the skin. In women, there may be increased
growth of facial and body hair, and menstrual periods
may become irregular or stop completely. Neurological
symptoms include difficulties with memory and neuromuscular
disorders.
Thyrotropin (TSH) secreting adenomas
Thyrotropin (TSH)-secreting pituitary adenomas are
a rare cause of hyperthyroidism. They account for less
than 1% of all functioning pituitary tumors and much
less than 1% of all cases of hyperthyroidism. Nevertheless,
the diagnosis should be considered in all hyperthyroid
patients, especially those with a diffuse goiter and
no extrathyroidal manifestations of Graves’ disease.vi
Gonadotropin-secreting Adenomas
Gonadotropin-secreting adenomas are nonfunctional,
or non-hormone producing and make up approximately 30%
of all pituitary tumors. They present in general as
a consequence of local mass effect. Patients often initially
present with complaints of headache from irritation
of the dura mater or fatigue from panhypopituitarism.
As the tumor extends to involve the optic chiasm, patients
will present varying degrees of visual loss. The classic
presentation of the visual deficit is a bitemporal hemianopsia,
but central scotomas and generalized blurring of vision
are sometimes the complaint. Panhypopituitarism as a
consequence of mass effect on the normal pituitary gland
can result in fatigue and sexual dysfunction, ranging
from decreased libido to lack of erectile function.(vii)
DIAGNOSIS
Diagnosis of pituitary disease is dependent on symptoms,
signs on examination, MRI findings and biochemical tests.
When pituitary tumor is suspected, a thorough family
history is an important first step in detecting risk
factors and symptoms. Physicians should ask if family
members have had a pituitary gland tumor, hyperparathyroidism,
multiple kidney stones, multiple stomach ulcers, hypoglycemia
(problems with glucose metabolism), or adrenal gland
tumors. A physical exam should yield several of the
myriad symptoms that indicate pituitary tumor. A neurological
exam, including tests for field of vision, hearing,
balance, coordination, reflexes and stigmata of endocrine
disease is also critical to an appropriate diagnosis.
MRI imaging is effective for finding most, but not all
pituitary tumors.
Endocrine testing includes serum hormone levels and
provocative tests of the hypothalamic-pituitary-target
organ axes. These tests assess pituitary dysfunction
and hypersecretion. Basal GH and IGF-1 levels are used
to screen for acromegaly, although lack of suppression
of GH levels during an oral glucose tolerance test can
be required to confirm the diagnosis. Serum PRL levels
greater than 200ng/ml are highly suggestive of a prolactin-secreting
adenoma.
The diagnosis of Cushing’s disease is more problematic.
Cushing’s disease, in part, is a diagnosis of exclusion.
Other causes of Cushing’s syndrome must be excluded,
including ectopic sources of ACTH, such as bronchogenic
carcinoma and pulmonary carcinoid. Conditions such as
obesity, alcoholism, and depression can also elevate
serum cortisol levels. Endocrinologic findings suggestive
of Cushing’s disease include an elevated 24-hour
urine free cortisol level, loss of the diurnal variation
in blood cortisol levels, and lack of suppression of
serum cortisol levels after low-dose dexamethasone administration.
Salivary cortisol levels and/or midnight serum cortisol
levels may need to be checked. Inferior petrosal sinus
sampling after corticotropin-releasing factor stimulation
may be required to confirm and localize the pituitary
source.(ix)
TREATMENT
Asymptomatic incidental microadenomas can be followed
with serial imaging studies. Symptomatic pituitary tumors
require medical or surgical intervention, either alone
or in combination. Radiotherapy and radiosurgery can
also be useful adjuncts. Regardless of the modality,
specific outcome measures are used to assess efficacy.
Therapeutic goals are improved quality of life and
survival; elimination of mass effect and reversal of
related signs and symptoms; normalization of hormonal
pituitary function; and prevention of recurrence of
pituitary tumor. Finally, pituitary lesions also require
definitive histological confirmation and characterization.(x)
Prolactinomas
Unlike other pituitary tumors, surgery usually is not
the first treatment for prolactin-secreting adenomas
(PRLs). Bromocriptine (Parlodel) and cabergoline (Dostinex)
are drugs that are so effective—both in blocking
prolactin production by these adenomas and preventing
growth of these tumors—that surgery usually is
not necessary. Cabergoline has an advantage of lasting
longer, so it does not need to be taken as often. Side
effects may be fewer with cabergoline.(xi)
According to the American Cancer Society, 80-90% of
patients are able to control their prolactin levels
with medication. The drugs are also effective in reducing
the size of prolactin-secreting macroadenomas. About
60 percent of these tumors shrink to less than half
their original size after medical treatment. Only about
15-20% of these tumors show no decrease in size after
treatment.
If successful, drug therapy can be continued for life.
Within three months of starting drug therapy, the blood
prolactin level is measured again and the MRI scan is
repeated to study efficacy. If little or no response
is achieved after six months or if serious side effects
occur, then surgery should be considered.(xii)
Growth Hormone-secreting Adenomas
Surgery is considered the best treatment. If it doesn’t
normalize the blood IGF-I levels, medical therapy can
be used. If neither can stop the tumor’s secretion
of too much growth hormone, then radiotherapy can be
administered.
Drugs such as bromocriptine or cabergoline may reduce
growth hormone levels in about 10-20% of patients. Unfortunately,
high doses are often needed to be effective but they
are not well tolerated by some patients.
Octreotide is a modified form of the natural hormone
somatostatin. In about 65% of patients, this medicine
blocks growth hormone production by adenomas and returns
insulin-like growth factor-I (IGF-I) to normal levels.
Unfortunately, it must be injected under the skin three
times per day. A newer drug called lanreotide has been
effective in suppressing growth hormone secretion in
European studies.
Both these drugs have side effects, such as nausea,
vomiting, diarrhea, stomach pain, dizziness, headache,
and pain at the site of injection. Recently, long-acting
versions of both of these drugs have become available.
Lanreotide can be given by injection every 21 to 28
days, and the octreotide can be given every month. Both
drugs are injected into muscle, usually in the buttocks.
A new drug called pegvisomant (Somavert) works by blocking
the action of growth hormone. The other drugs work by
preventing its secretion. Pegvisomant has been very
successful, but so far has been studied mainly in people
who have failed other treatments such as surgery and/or
radiation.(xiii)
Corticotropin (ACTH)-secreting Adenomas
Several therapies are available to treat the ACTH-secreting
pituitary adenomas of Cushing’s disease. The first
treatment is surgical removal of the tumor. After curative
pituitary surgery, the production of ACTH drops below
normal. This is a natural, but temporary, drop in ACTH
production. Patients are given a synthetic form of cortisol
(such as hydrocortisone or prednisone), and most patients
can stop this replacement therapy in less than a year.
When surgery has failed or in the case where patients
are not suitable candidates for surgery, fractionated
radiotherapy and stereotactic radiosurgery are other
possible treatments. Improvement occurs in 40- 50% of
adult cases and up to 80% of childhood cases. It may
take several months or years before patients feel better
from radiation treatment alone. However, the combination
of radiation and the drug mitotane (Lysodren®) can
help speed recovery. Mitotane suppresses cortisol production
and lowers plasma and urine hormone levels. Treatment
with mitotane alone can be successful in 30-40% of patients.
Other drugs used alone or in combination to control
the production of excess cortisol are aminoglutethimide,
metyrapone, trilostane and ketoconazole. Each has its
own side effects that should be considered when prescribing
therapy for individual patients.(xiv)
In some cases, if pituitary surgery is not successful,
surgical removal of the adrenal glands (bilateral adrenalectomy)
may take the place of drug therapy.
Gonadotropin-secreting Adenomas
The selection of treatment will depend on tumor size,
the progressive course of the disease, and anatomical
structures affected by the tumor extension. The standard
treatment is surgery, especially if there is impaired
vision or cranial nerve palsy. Radiosurgery or conventional
radiation therapy may be indicated in those patients
with residual pituitary tumor following surgical debulking.
The efficacy of medical therapy in these patients is
not established.
SURGERY
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traditional sublabial transsphenoidal approach is
performed through an incision under the upper lip.
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Neurosurgeons currently approach the sell turica by
either the transcranial or the transsphenoidal route.
The transsphenoidal approach is effective in all but
those tumors that have marked expansion into the anterior
or middle cranial fossae. In such circumstances, craniotomy
by either a subfrontal or pterional approach in indicated.
Occasionally, a combined transsphenoidal and transcranial
approach is used.
Through progressive refinements in technique, the transsphenoidal
approach has become a versatile method for treating
pituitary tumors. Most often, the approach to the sphenoid
sinus can be accomplished endonasally.
Due to the minimally invasive nature of the transsphenoidal
approach, patients can expect a two or three-day hospital
stay, followed by three to four weeks of at-home recovery.
“A pituitary tumor in the ‘high rent district’
next to the optic nerve and the carotid artery is tricky
business,” Dr. Rosseau adds. “The endonasal
transsphenoidal approach helps to minimize many of the
risks.”
Outcome
Nonfunctioning pituitary adenomas most often present
as macroadenomas and cause visual field deficits and
hypopituitarism. Surgery improves or prevents progression
in visual loss in approximately 90% of patients with
visual deficits. Twenty-seven percent of patients presenting
with hypopituitarism experience postoperative normalization
of hormone secretion. Operative mortality for these
larger and often more invasive tumors is higher than
for the hyperfunctioning adenomas and reaches just over
1%. For similar reasons, tumor recurrence is also an
issue. Ten-year recurrence rates approach 20%, although
only 6% require reoperation. Long-term followup finds
83% of patients alive and well without evidence of disease.
Transsphenoidal surgery obtains remission in 88% of
patients with microadenomas and 65% of patients with
macroadenomas. Acromegalic symptoms are improved in
95%. Ninety-seven percent of patients have preserved
normal pituitary function. Surgical management of Cushing’s
disease achieves a 91% remission rate for patients with
microadenomas and 65% for those with macroadenomas.xv
Complications
The overall mortality rate for transsphenoidal surgery
is less than 0.5%, but is slightly higher for nonfunctioning
macroadenomas. Major morbidity (cerebrospinal fluid
leak, meningitis, stroke, intracranial hemorrhage, and
visual loss) occurs in between 1 and 2% of cases. Minor
complications (sinus disease, nasal septal perforations
and wound issues) occur in approximately 6.5%.xvi
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