Approach to Pituitary

Adenoma
Classification
Pathological classification
◦ Non-functional versus functional

◦ Anatomical and neuro-radiological appearance:

based on tumor size and degree of local invasion.

◦ Histological appearance: based on immuno-cyto

chemical characterization.

◦ Ultrastructural features: based on electron

microscopic features. 2
Tumor Size

◦ Micro-adenoma: <1cm

◦ Macro-adenoma: >1cm

3
 Presentation
◦ Most clinically non-functional pituitary adenomas
(CNFPAs) present late because they either do
not secrete any hormones or they secrete
functional hormones inefficiently. They rarely
produce intact glycoprotein FSH and LH, but
more commonly produce varying combinations
of either FSH beta subunit and/or LH beta
subunit along with the common alpha subunit.
◦ Mean age of presentation is 50 to 55 years.
4
History
◦ Pituitary adenomas may be found incidentally on
imaging, or may present with symptoms and signs
of mass effect or neuroendocrine changes.
◦ Headaches are common (19% to 75%)
◦ Tumor growth into the third ventricle may cause
hydrocephalus and associated symptoms such as
headache, imbalance, and urinary incontinence.

5
History
◦ Lateral tumor growth into the cavernous sinus
may cause double vision from third, fourth, and
sixth cranial nerve palsies and facial pain and
paresthesia from palsy of the V1 and V2
branches of the fifth cranial nerve.
◦ Seizures may occur from temporal lobe
involvement.
◦ Recurrent sinusitis and CSF rhinorrhea may
result from growth into the sphenoid sinus.
6
History
◦ Patients may present with features of
hypopituitarism.
◦ The gonadotrophs and somatotrophs appear
most susceptible to the local pressure damage
from a clinically non-functional pituitary adenoma
(CNFPA).
◦ Hypogonadism in men presents with loss of
secondary sexual characteristics, mood
impairment, loss of libido, erectile
dysfunction, infertility, anaemia, loss of
muscle mass, and osteopenia. 7
History
◦ In women, amenorrhoea, diminished libido,
infertility, hot flushes, osteopenia, and breast
atrophy are present.
◦ GH deficiency causes truncal obesity; fatigue
associated with diminished effort tolerance,
diminished muscle mass and increased fat
mass, osteopenia, depression, and abnormal
lipid profile.

8
History
◦ Hypothyroidism causes fatigue,
constipation, weight gain, cold intolerance,
dry skin, hair loss, bradycardia, memory loss,
and depression.
◦ Adrenal insufficiency causes fatigue, nausea,
anorexia, weight loss, hyponatraemia,
weakness, and trembling. There is typically no
hyperkalaemia because the mineralocorticoid
pathway is intact and there is no
hyperpigmentation.
9
Pituitary Apoplexy
◦ May be the presenting clinical picture with severe
headache of sudden onset, fever, nausea and vomiting,
meningismus, altered level of consciousness, visual
disturbances, and hypopituitarism. Clinically significant
pituitary apoplexy is a rare event in patients with
pituitary micro-adenomas.

◦ The risk of apoplexy is estimated to be from 0.4% to

9.5% during a mean follow-up of 2 to 6 years. It is due
to a rapid enlargement of the pituitary as a result of
either hemorrhage and/or infarction of the tumor.
10
Pituitary Apoplexy
◦ While most cases of pituitary apoplexy are
spontaneous, precipitating factors may include head
injury, anticoagulant therapy, dopamine agonists,
radiotherapy, or dynamic endocrine tests.

11
Examination
◦ At presentation 18% to 78% have visual field
defects as a result of visual pathway
compression, manifesting most commonly as
bitemporal hemianopia with chiasmal
compression. Patients may have diminished
visual acuity; visual field loss typically starts
with bitemporal superior quadrantanopia.
◦ Cranial nerve palsies involving third, fourth, fifth
(V1 and V2), and sixth cranial nerves and
mydriasis associated with third nerve palsy may
be present. 12
Examination
◦ Endocrine-related findings in patients with
pituitary adenoma include signs of
hypogonadism (decreased facial and body hair,
gynecomastia, decreased muscle mass, soft
testicles in men and breast atrophy in
women); hypothyroidism (dry skin, coarse hair,
puffy face, loss or thinning of eyebrows); and
growth hormone deficiency (loss of muscle
mass, increased abdominal obesity).
◦ Pallor and increased skin wrinkling are
characteristic findings in patients with 13
Routine blood tests
◦ Basic metabolic panel and CBC should be
done initially.
◦ Hyponatremia may be seen in adrenal
insufficiency and hypothyroidism and is also
associated with symptoms such as nausea,
vomiting, headache, and malaise.

15
Morning Serum Cortisol
◦ Low — A serum cortisol value of
≤3 mcg/dL (83 nmol/L, normal range 5 to
25 mcg/dL [138 to 690 nmol/L]),confirmed by a
second determination, is strong evidence of
cortisol deficiency, which in a patient with a
disorder known to cause hypopituitarism is
usually the result of that disorder.
◦ A serum ACTH value not higher than normal is
inappropriately low and establishes the
diagnosis of secondary adrenal deficiency (i.e,
pituitary or hypothalamic disease) 16
Prolactin
◦ Mild to moderate hyperprolactinemia may be
present (<4348 picomol/L [<100 nanogram/mL
{<100 microgram/L}]).
◦ With the exception of patients on metoclopramide
and antipsychotics, prolactin level >4348
picomol/L (>100 nanogram/mL [>100
microgram/L]) is almost always diagnostic of a
prolactinoma.

17
GH and insulin-like growth factor-1 (IGF-1)
◦ Random GH levels may be low and IGF-1 may be
normal in up to 65% of patients with GH deficiency.
◦ The presence of 3 or more anterior pituitary
hormone deficiencies in the presence of low IGF-1
usually indicates the presence of GH deficiency and
thus may obviate the need for further testing.
◦ However, a stimulated GH level with either an
insulin tolerance test (ITT), glucagon, or
arginine/GHRH is typically required for the
diagnosis.

18
FSH, LH, hCG
◦ Low serum testosterone in men (estradiol in
women) accompanied by normal/low FSH and
LH levels are consistent with gonadotrophin
deficiency in males and amenorrhoeic pre-
menopausal women.
◦ Failure to elevate FSH and LH in post-
menopausal women is also consistent with
gonadotrophin deficiency.
◦ The presence of regular menses almost always
indicates a normal gonadotrophin axis.
19
Thyroid Function Tests
◦ If secondary hypothyroidism is clinically
suspected, TSH and free T4 (or free T4 index)
should be measured together.
◦ Typically patients have a low or normal TSH
along with a low free T4 level, in contrast to
patients with primary hypothyroidism, in whom
TSH is elevated.

20
Ophthalmic Evaluation
◦ Eye examination and formal visual field testing
(Humphrey or Goldmann visual field test) are
indicated if imaging shows the adenoma is
causing pressure on, or has contact with, the
optic chiasm, in order to document visual acuity
and field deficits.

21
Differential Diagnosis
Prolactinoma
◦ The presence of galactorrhoea suggests
prolactinoma.
◦ While macroprolactinomas may present with
similar clinical pictures to non-functional
pituitary macro-adenomas, microprolactinomas
in pre-menopausal women may present with
amenorrhoea and galactorrhoea, and with
impotence and lack of libido in men.
◦ Hypogonadism in non-functional pituitary micro-
adenomas is rare.
23
GH-secreting adenoma
(acromegaly)
◦ These are macro-adenomas in about 75% of
cases. Patients typically have coarsening of
facial features and acral enlargement.
◦ Other signs and symptoms may include skin
tags, macroglossia, hypertension, arthropathy,
hyperhidrosis, symptoms associated with sleep
apnea, and glucose intolerance/diabetes.

24
ACTH-secreting tumor
(Cushing Syndrome)
◦ These tumurs are typically micro-adenomas
and cause classic symptoms of Cushing
syndrome, including skin atrophy, easy
bruising, facial plethora, central adiposity,
muscle wasting, and wide (>1 cm) purplish
striae.

25
Other differentials
◦ TSH-secreting adenoma
◦ Rathke’s cleft cyst
◦ Craniopharyngioma
◦ Meningioma
◦ Hypophysitis
◦ Sarcoidosis
◦ Infections (TB)
◦ Germinoma
◦ Metastatic lesions
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Management
Approach
◦ The goals of therapy for clinically non-functional
pituitary adenomas (CNFPAs) with mass effect
are to remove the tumor as completely as
feasible, reverse any visual or other
neurological deficit, reverse any hormonal
deficit, and preserve the function of the
unaffected pituitary gland.
◦ Observation alone is indicated for clinically non-
functional pituitary micro-adenomas and macro-
adenomas without mass effect and not abutting
optic chiasm. 28
Approach
◦ Therapy is directed by the size of the tumour,
presence of parasellar extension including
compression of the optic pathway and/or
invasion of cavernous sinuses and sphenoid
sinus, complications such as pituitary
apoplexy, and experience of the
neurosurgeon.
◦ Multidisciplinary clinical care is preferred.
◦ Therapeutic options may include observation
alone, surgery with or without postoperative
radiotherapy, and medical therapy. 29
Observation
◦ Micro-adenomas generally do not grow and
even if they do, they usually do not impair visual
fields or cause hypopituitarism.
◦ In one study, among 166 patients with micro-
adenomas, 17 (10.2%) showed a 10% increase
in tumor size (3%-40%) over a mean follow-up
of 4.3 years. The majority (80%) remained
unchanged, while 10% demonstrated a
reduction in tumour size. [56]

30
Observation
◦ For patients with clinically non-functional
pituitary micro-adenomas, MRI may be
repeated after 1 year initially, with further MRI
studies only if the patient develops symptoms
suggestive of mass effect.

31
Observation
◦ Macro-adenomas have a propensity to grow:
among 356 macro-adenomas, 87 (24%)
increased in size, 45 (13%) decreased, and 224
(63%) remained unchanged over a mean
follow-up of 4.3 years.
◦ For patients with clinically non-functional
pituitary macro-adenomas, an appropriate
schedule would be to repeat the MRI in 6
months, then yearly for 5 years, followed by
every 2 to 3 years if stable.
◦ Surgery is indicated if there is tumor growth. 32
Trans-sphenoidal surgery
◦ Indicated as first-line therapy for:
◦ Patients with symptomatic pituitary apoplexy
◦ Clinically non-functional pituitary macro-
adenomas that abut the optic chiasm, and
those with mass effect such as visual field
defect
◦ Tumors that demonstrate progressive increase
in size.

33
Radiotherapy
◦ Radiotherapy is typically used postoperatively
when there is significant residual tumor
mass, particularly tumor invading the
cavernous sinus, or to treat a recurrence.
◦ It may be used for tumor growth control in those
who are poor surgical candidates.

34
Radiotherapy
◦ Postoperative radiotherapy seems to reduce
recurrence, with an overall tumour recurrence
rate ranging between 2% and 36%. [63]
◦ About 10% of 224 patients irradiated
postoperatively, compared with 25% of 428
patients not irradiated, experienced tumour
recurrence. [51]

35
 Radiotherapy
◦ Recent reports incorporating the use of early
postoperative MRI scans evaluated the impact of
postoperative radiotherapy on residual tumour
remnant. Among those with visible remnant tumour on
MRI, 23% of 83 patients who received routine
radiotherapy experienced tumour growth, compared
with 41% of 200 patients who did not receive
radiotherapy.
◦ A near total tumour resection and the use of
postoperative radiotherapy seem to reduce the risk of
tumour recurrence and/or regrowth, although this is
generally used postoperatively for residual tumour and
36
to treat recurrence.
Treatment
Microadenoma
◦ Observation: There are good observational
data that the natural course of these tumors is
such that observation alone should suffice in
their management.
◦ About 10% of micro-adenomas grow, 6%
shrink, and 84% remain unchanged.

38
 Macro-adenoma without mass
effect and not abutting optic
chiasm
1st Line • Observation

Adjunct • Hormone replacement

• Evaluation for
trans-sphenoidal
Adjunct surgery

39
Macro-adenoma without mass
effect but abutting optic chiasm
◦ 1st line: Trans-sphenoidal surgery
◦ Adjunct: Hormone replacement

◦ 2nd line: Observation (pts not willing to proceed

with surgery and/or significant co-morbidities)
◦ Adjunct: Hormone replacement
◦ Adjunct: Radiotherapy (preferably via stereotactic gamma
knife, may be indicated if there is significant residual tumor after surgery
or with the first sign of recurrence after an initially successful tumor
removal)
40
Macro-adenoma with mass effect
◦ 1st line: Trans-sphenoidal surgery
◦ Adjunct: Hormone replacement
◦ Adjunct: Dopamine agonists or somatostatin
analogs

41
Temozolomide
◦ Temozolomide, a second generation alkylating agent of
the imidazotetrazine class, may be considered in
patients with aggressive pituitary adenomas.

◦ Compared with prolactinomas (73%) and ACTH-

secreting tumours (60%), CNFPAs exhibit a lower
response rate (40%). A positive response is typically
evident in the first 3 months of therapy which may be
dramatic and sustained.

43
References
◦ Chanson P, Salenave S. Diagnosis and treatment of pituitary adenomas. Minerva Endocrinol. 2004 Dec;29(4):241-75.
◦ Sibal L, Ball SG, Connolly V, et al. Pituitary apoplexy: a review of clinical presentation, management and outcome in 45
cases. Pituitary. 2004;7(3):157-63.
◦ Dekkers OM, Pereira AM, Romijn JA, et al. Treatment and follow-up of clinically nonfunctioning pituitary
macroadenomas. J Clin Endocrinol Metab. 2008 Oct;93(10):3717-26.
◦ Shomali ME, Katznelson L. Medical therapy of gonadotropin-producing and nonfunctioning pituitary adenomas.
Pituitary. 2002;5(2):89-98.
◦ Dekkers OM, Hammer S, de Keizer RJ, et al. The natural course of non-functioning pituitary macroadenomas. Eur J
Endocrinol. 2007 Feb;156(2):217-24.
◦ Karavitaki N, Collison K, Halliday J, et al. What is the natural history of nonoperated nonfunctioning pituitary
adenomas? Clin Endocrinol (Oxf). 2007 Dec;67(6):938-43.
◦ Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008
Mar;37(1):151-71.
◦ Dekkers OM, Pereira AM, Roelfsema F, et al. Observation alone after transsphenoidal surgery for nonfunctioning
pituitary macroadenoma. J Clin Endocrinol Metab. 2006 May;91(5):1796-1801.
◦ Mortini P, Losa M, Barzaghi R, et al. Results of transsphenoidal surgery in a large series of patients with pituitary
adenoma. Neurosurgery. 2005 Jun;56(6):1222-33.
◦ Brada M, Jankowska P. Radiotherapy for pituitary adenomas. Endocrinol Metab Clin North Am. 2008 Mar;37(1):263-75.
◦ Pivonello R, Matrone C, Filippella M, et al. Dopamine receptor expression and function in clinically nonfunctioning
pituitary tumors: comparison with the effectiveness of cabergoline treatment. J Clin Endocrinol Metab. 2004
Apr;89(4):1674-83.
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