Pituitary adenoma

Management of Pituitary
Adenoma
- By Sumit Agarwal
Junior resident -3
Moderator: Dr Himanshu Mishra sir

Pathology
 Low proliferate activity
 Mitosis rare
 Cytological characteristics that are typically used to assess growth
in malignancy are unreliable in pituitary tumors
 pituitary adenoma can not be classified as benign or malignant
based on pathologic criteria
 Local invasion to bone and soft tissue is common in benign
adenoma
 Higher Ki-67 values seen in frankly invasive adenoma

Classification
 Pituitary tumors can be classified into three groups according to their
biological behavior:
 Benign,
 Invasive adenoma, and
 Carcinoma.
 Invasive adenomas-
may invade into the dura mater, cranial bone, or sphenoid sinus.
 Carcinomas account for 0.1% or 0.2% of all pituitary tumors.

Diagnostic work up
 History & complete physical examination
 Endocrine evaluation: diurnal variation of hormones,
age, gender, pregnancy and menopausal status
 Radio logic studies
MRI –procedure of choice
 CT- ventriculogram
 Skull film
 Special test
 Visual acuity and field vision

Sign and Symptoms
Mass symptoms Hypopituitarism
Endocrine symptoms

Clinical features
 Characteristic-presenting features of pituitary adenomas
 Inappropriate pituitary hormone secretion and
 visual field deficits
Signs and symptoms of pituitary disease include:
 Cranial nerve palsies.
 Temporal lobe epilepsy.
 Hydrocephalus.
 Cerebrospinal fluid rhinorrhea.

 Prolactinomas
 Headache.
 Visual field deficits.
 Oligomenorrhea or amenorrhea.
 Reduced fertility.
 Galactorrhea in the estrogen-primed female breast.
 Loss of libido.
 Erectile dysfunction.

 Signs and symptoms of corticotroph adenomas :
 Headache.
 Centripetal fat distribution.
 Neuropsychiatric symptoms.
 Striae.
 Skin thinning.
 Hirsutism.
 Osteopenia.
 Proximal myopathy
 Ability to easily bruise.

 Signs and symptoms of somatotroph adenomas :
 Headache.
 Growth of hands and feet. .
 Jaw growth and prognathism
 Carpal tunnel syndrome.
 Snoring and obstructive sleep apnea.
 Osteoarthritis and arthralgia.
 Excessive sweating.
 Dysmorphophobia.
 Coarsening of facial features

 Signs and symptoms of thyrotroph adenomas :
 Palpitations.
 Tremor.
 Weight loss.
 Insomnia.
 Hyper defecation.
 Sweating.

Signs and symptoms of nonfunctioning adenomas :
 Headache.
 Visual field deficits.
 Pituitary insufficiency,
- due to compression of the pituitary stalk or
- destruction of normal pituitary tissue by the tumor,
- predominantly manifests as secondary hypogonadism.

MRI
 A MRI scan is now considered the imaging modality of choice for the
diagnosis of pituitary tumors (pituitary adenomas, carcinomas and
metastases) because of its
 Multiplanar capability and
 Good soft tissue contrast enhancement.
 A 1-mm thin slice is typically used to obtain optimal resolution

 A wide variety of endocrinologic tests are available for patients
whose history and physical examination
are consistent with pituitary adenoma.
 Serum PRL levels greater than 200ng/ml are highly suggestive of a
prolactin-secreting adenoma.
 OGTT
 The normal level of serum GH is 3 to 5 ng/mL
 Normal – GH < 2 ng/ml
 Failure to suppression <1 microgm
 Elevated 24-hour urine free cortisol level,
 loss of the diurnal variation in blood cortisol levels

Management
 Therapeutic Goals for Pituitary Adenomas
1. Eliminate mass effect and reverse related signs and symptoms
2. Normalize hormone hyper secretion and reverse secondary
effects
3. Preserve or recover normal pituitary function
4. Improve quality of life

 Current treatment strategies of pituitary adenomas include
 Surgery
 Radiotherapy
 Medical
 The treatment choice depends on the tumor size, surgical
accessibility, functional status, and symptoms.

Surgery
 All symptomatic Pituitary adenoma (micro or macro adenoma except
prolactinoma),or nonfunctional macroadenoma
Initial TOC
Resection
 Patients with prolactin-secreting adenomas might require surgery if either
intolerant or resistant to medical therapy
 Advantages of Surgery :
 Mass effects can be decompressed quickly
 Endocrine hyper-secretion decreased or eliminated
 Existing pituitary function retained or improved rapidly


Surgery
Trans-sphenoidal Trans cranial
(Preferrred)
Contraindication
1. Little enlargement of sella relative to large suprasellar mass
2. Extra seller extension to middle fossa
3. Unusually fibrous tumor
4. Para seller aneurysm

Mortality rate of approximately 0.5%
Major complications
 Meningitis
 Cerebrospinal fluid leak
 Hemorrhage
 Stroke
 Visual loss
Approximately 1.5% of the procedures

Management of Non Functioning Adenomas

Management of Functioning Adenoma

Dopamine agonist-
 Cabergoline
 Bromocriptine
 Lysurite
 Pergolip
Medical Management

Cabergoline:
 Dose: 0.25 mg twice weekly
 For 2 years
 recommended over bromocriptine due to higher potency and
effectiveness .
 Assessment with hormonal status and MRI brain
 Side effects
May require echocardiography to monitor for valvular defects if used in
high doses for prolonged period of time
Others:
• Nausea.
• Vomiting.
• Heartburn.
• Constipation.
• Tiredness.
• Dizziness.

Bromocriptine:
 Bromocriptine-rapid normalization of prolactin levels; 80% to 90% of
patients
 Bromocriptine reduces tumor size, near 80% of cases
 A/E -transient nausea and vomiting
 Orthostatic hypotension may also occur at the initiation of therapy
 more nausea than cabergoline
 Less effective than cabergoline

 Cabergoline is as effective as bromocriptine in lowering prolactin
levels and reducing tumor size
 Dose 0.25mg twice weekly for 2 years
 Biochemical recurrence rates 2 to 5 years after withdrawal-
31% in microprolactinomas, 36% in macroprolactinomas

 Transsphenoidal Resection
 Indication-
 rapidly progressive vision loss
 increase in adenoma size despite dopamine agonists,
 intolerance or inadequate hormonal response to
medical therapy
Surgery

 About 74% of microprolactinomas, 32% of macroadenomas,
prolactin levels normalize,1 to 12 weeks postsurgery
 20% of patients present a biochemical recurrence within 1
year
 Prolactin levels above 20 ng/mL typically worse

Radiotherapy
Indication –
Tumour progression after surgery

 Patients receiving dopamine agonists at the time of
radiosurgical treatment had a significantly worse
outcome
 2 month gap between Medical Therapy & Rdiotherapy
was suggested

Mean prolactin levels after radiation ranged from 25% to 50% of
the pretreatment level
With few patients achieving normal values
The mean time required to reach normal prolactin levels was
7.3 years

Goals of treatment-
 The reduction of circulating hormone levels
 reversal of mass effect
Growth Hormone Secreting Tumors

• Surgical intervention alone provides the most rapid means of
achieving both goals
• Transsphenoidal microsurgery-The standard surgery
for most tumors
• Particularly effective in selective removal of microadenomas
• But it also is used for adenomas that extend outside the sella.

 Adjuvant therapies for patients with residual tumor
 Persistently elevated GH levels after surgery
 Radical alternatives for medically inoperable patients
 The most significant predictive factors- tumor size and pretreatment
GH levels.
Radiotherapy

 GH levels decrease over a period of several years
 A 50% reduction in serum GH is expected after approximately 2
years of RT
 By 10 years after radiation therapy, 60% to 100% of patients have
GH levels <10 ng/mL

Medical Therapy
Somatostatin analogs (octreotide & lanreotide)
 Reduce GH and IGF-I levels, 50% to 60% of patients who have
failed surgery
Tumor shrinkage occurs in 30% to 45% of patients
A/E-
 Transient abdominal cramps
 Malabsorptive diarrhoea,
 Nausea of mild-to-moderate intensity
 Gallbladder sludge or stones

GH receptor antagonist-
o Pegvisomant, a genetically engineered GH receptor
antagonist
Daily injections of pegvisomant resulted in normalization
of IGF-I in 89% of patients
Effective in reducing serum IGF-I
concentrations
A/E-diarrhea, nausea, flu syndrome, and abnormal liver
function tests

Hormonal cure rates range from 57% to 90%
Highest success rates seen in patients harboring well-
defined microadenomas
Recurrence rates after achieving surgical remission range
from 2%to 25%
Surgical Management –
Selective Transsphenoidal removal of the ACTH-secreting
adenoma remains the standard of care

Bilateral adrenalectomy is reserved for patients who have
failed other treatment modalities
Induces a predictable and rapid hormonal response
Patients subsequently require lifelong treatment with
glucocorticoids and mineralocorticoids
Bilateral adrenalectomy can also result in Nelson syndrome
local progression of the pituitary tumor with characteristic
skin pigmentation resulting from the high concentrations of
corticotropin.

Adjuvant or definitive radiotherapy with doses of 35 to
50 Gy have provided hormonal control rates of 50% to
100%
Most remissions achieved in the first 2 years
Radiosurgery has been mainly used as salvage therapy after
failed or incomplete transsphenoidal surgery
Radiotherapy

Reserved for patients who fail either surgery or radiotherapy
Lifelong and associated with important side effects
Agents that modulate pituitary ACTH release-
cyproheptadine, bromocriptine, somatostatin, and
valproic acid provide poor response rates with only
modest effect.
Medical Therapy

Agents that inhibit steroidogenesis-
Ketoconazole, mitotane, trilostane, aminoglutethimide,
and metyrapone
With important side effects and limited efficacy

Nelson Syndrome
 Some patients with Cushing disease do not achieve remission after
surgery or irradiation or require rapid normalization of hypercortisolism.
 Bilateral adrenalectomy (BLA) via the laparoscopic approach is
associated with a significantly reduced morbidity compared with the
traditional open approach.
 Following BLA, patients are at risk for adrenal crisis with the concern of
developing Nelson syndrome,

 Characterized by hyperpigmentation, rapid growth of the adenoma, and
invasion of the tumor into the parasellar regions.
 The few reports of SRS for Nelson syndrome have resulted in endocrine
remission rates ranging from 36% to 67%.
 Tumor control was 92.5% in one study.
 More recent experience showed all 14 patients had decrease in ACTH
level, although only 2 patients (14.3%) had normalized ACTH level 13 and
14 years after SRS.
 Temozolomide can be an effective treatment option for invasive
adenomas in Nelson syndrome.1

Thyroid-Stimulating Hormone–Secreting Adenomas
 Thyroid-stimulating hormone-secreting adenomas are rare (0.5% to
1.5% of all pituitary tumors) .
 Typically present as macroadenomas with mass effect and features of
thyrotoxicosis.
 Surgical removal of the TSH-secreting adenoma is the best treatment
option after the hyperthyroidism has been controlled with medications.

Pituitary Carcinomas and Aggressive Pituitary
Tumors
 Pituitary carcinomas are very rare (< 0.5% of all pituitary tumors).
and have clinical features of pituitary adenomas, with most
secreting prolactin or ACTH.
 Although most progress from previously aggressive behaving
pituitary tumors.
 The diagnosis is based purely on the presence of CSF cytology

The overall prognosis for these tumors is poor despite aggressive
treatments that have included radiation therapy with mean survival
of 1.9 years.

Radiotherapy
Aims
 To control tumor cell proliferation
 eradicate any significant residual tumour
 Prevent re growth
 In endocrine active tumors
 Further decrease persistently elevated circulating hormone

 Indications of post op Radiotherapy
 Incomplete resection - most common indication
 Recurrence
 Primary RT
Medically inoperable
 Who refuses to surgery
Radiotherapy

For two-dimensional planning in which an eye-sparing anterior or vertex
beam will be used, the patient is positioned supine with neck flexed and
the head at a 45-degree angle
OR
Patient is generally positioned with the head and neck in a neutral
position.
Simulation

Technique
 Position - supine
 Head and neck flexed
 Head typically held at 450
 Tilting –head base plate
immobilization system
 All patients were treated in a
supine position with flexion of the
head so that base of the skull
was in right angle to the couch
and parallel to the central plane

 Two field technique - 2 lateral opposed
 Three field technique
 2 lateral opposed and 1 vertex field
15-30 0 wedge
• Typically 5x5 cm field used,
centered on sella

Supine
Head and neck neutral position

Gantry rotation to
opposite side
Gantry Angle = CR
Couch rotation 900

Radiation delivered to the temporal and frontal lobes as a
consequence of treating a pituitary tumor
with four radiotherapy techniques using 6-MV photons

Dose
 Show dose response rate depending on tumor type
XRT Local tumor control Bio. control
1.8Gy/#
Nonfunctioning 45-50.4 Gy 95% NA
Functioning 50- 5 Gy 90-95% 33-95%
Older series established that
 Dose <40 Gy a/w poor local control
 Dose >50.4 Gy a/w higher complication rate with no proven increase
in in local control

 (GTV) is the pituitary adenoma, including any extension into adjacent
anatomic regions.
 (CTV) limited to a 5-mm margin around the tumor is adequate
 With invasive tumors, such as those involving the sphenoid sinus,
cavernous sinus, or other intracranial structures
 There is greater uncertainty that must be considered in determining the
volume to be included.
 The entire contents of the sella and the entire cavernous sinus are
included in the CTV.

 The volumes described are then defined on the MRI but reviewed on
the CT.
 Normal structures to be contoured include
 the eyes (lenses),
 nerves,
 optic chiasm,
 brainstem, and
 temporal lobes

 Pituitary adenomas show dose-response rates that depend on tumor
type
 Non functioning tumors are usually controlled with 45 to 50.4 Gy using
daily fractions of 1.8 Gy.
 Functioning tumors require slightly higher doses, typically 50.4 to 54 Gy
Dose and Fractionation Schedule

SRS and SRT
 Principles
 Non-coplanar beams
 They interact with each other at isocentre
 At a point short distance from isocentre –no overlap
 leading to extreme concentrated radiation energy at this
point with sharp fall of dose outside the target.

 Stereotactic radiosurgery
 Technique involving high dose of radiation delivered in single
session to the tumor while reducing the dose to normal brain
tissues
 Stereotactic radiotherapy
 Type of fractionated radiotherapy to irradiate a stereo tactically
defined target

 Advantages
 Rapid dose fall off outside the target volume
 Conformality of prescribed dose to the target volume
 Different machines use
• Gamma Knife
• LINAC-based systems (X-Knife)
• Cyber Knife

Patient selection criteria
 Radio logically distinct adenoma
≤ 3 cm (SRS) or Larger lesions (SRT)
 Contraindications of SRS
 Lesions involved or very close optic apparatus
 Size > 3 cm

Dose
RADIOSURGERY DOSE
optic chiasma < 9Gy
NFPA 12- 24 Gy to margin
FPA 25-30 Gy to margin

Role of proton beam
 Rate of energy loss
 Proportional to the square of
particle charge and inversely
proportional to square of its
velocity
 As particle slows down rate of
energy loss increases i.e.
absorbed dose increase
 Bragg peak –
 The ability to concentrate dose
inside the target volume and
minimize dose to surrounding
normal tissue
Dose
Depth in water

 PTV - all gross visible tumor (or all intrasellar contents with micro
adenomas) with a 5-mm margin
 Encompasses by the 90% isodose;
 The total number of treatment fields varied from 2 to 7
 The most common arrangement included 4 fields,
 An appropriate modulator wheel was chosen to spread out the
proton Bragg peak to the required size
 Energy -either 155 or 200 MeV depending on the required beam
penetration.

Disadvantages
 High cost of installation

Complications of radiotherapy
 Hypopituitarism
 Decreased Vision
 Carcinogenesis
 Radiation necrosis

Hypopituitarism
Most common complication,seen in 10%to 30% case by perez et all
Because radiation target volume include entire pituitary and
significant portion of hypothalamus virtually in all patients.
The time to development of RT-induced hypopituitarism following
therapy varied from 6 months up to a decade.
Rate increases with time and may be detected years after RT
Patients need to be tested at lest yearly

 In patients who developed hormone deficiency
 The first is usually GH
 Next hormones lost are gonadotropes and finally
either thyrotropins or adrenocorticotropins
 Surgery alone carries lower risk than RT
 Radiotherapy alone has lower risk than when RT
and surgery combined
 There is no doubt that it is a relatively common side
effect following RT, but the patients have no change in
the quality of life when hormone deficiencies are suitably
replaced.

Vision loss
 Rare
In fact Radiotherapy has been documented to improve tumour
related visual field and visual acuity defects in the majority
patients and stabilize the visual defects in the remainder patients
Emami et all. QUANTEC data

Carcinogenesis
• Extremely rare
• However as patients have long life expectancy
after pituitary irradiation, it is important to
understand the risk

Second Tumor Risk With Modern Radiotherapy for Pituitary
Adenomas
K. M. Winkfield et al. Harvard Radiation Oncology
Program, Boston, MA,
Purpose/Objective's:
 Technological advances have markedly improved conformal delivery of
radiation therapy.
 Acute treatment- related adverse effects are reduced; however, the impact
of second malignancy risk due to low dose irradiation of normal tissues is
unknown.
 This study was designed to estimate the risk of radiation-induced tumors
following treatment of pituitary adenoma.

 Materials/Methods: A standard case of a patient with a pituitary adenoma
with indication for fractionated radiation therapy was planned using 6
different dosimetric techniques:
 2-field conformal photon plan,
 2-field conformal proton plan, and
 3-field conformal proton plan.
 3-field conformal photon plan,
 5-field intensity-modulated radiotherapy with photons (IMRT),
 stereotactic radiotherapy with photons using 4 arcs (SRT),
 The excess risk of radiation-induced second tumors in the brain was
calculated using the corresponding dose-volume histograms for the whole
brain and based on the data published by the United Nation Scientific
Committee on the Effects of Atomic Radiation (UNSCEAR) and a risk model
proposed by Schneider.

 Results: The excess risks of radiation-induced second tumors in the
volume of the whole brain per 10,000 patients per year are:
 2-field protons -1.6
 2-field photon -4.7,
 3-field photon- 9.6,
 3-field protons -11.1
 IMRT -29.5,
 SRT -32.1,
 Two-field techniques had the lowest risk for second tumors but
were also less conformal and delivered greater excess dose to
the temporal lobes.

Radiation necrosis
Also rare complication
Radiation necrosis is not expected with these
doses(2Gy/#), particularly in the era of high energy
Linac and modern radiotherapy technique

Prognostic factors
 Type of adenoma
 Extent abnormality at the time of diagnosis
 Pretreatment hormone level
 How much reversible is injury due to mass
 Young age (<50 yrs)-with residual disease have faster re
growth of tumour than their older counter part

PROGNOSTICFACTORS AND RESULTS OF RADIATION THERAPY IN THE
MANAGEMENT OF PITUITARY ADENOMA : FOLLOWING TUMOR SIZE IN
COMPARISON WITH ENDOCRINE HYPERACTIVITY.
Sasaki Ryohei,et al. Department of Radiology, Hyogo Pref.Tsukaguti Hospital
 The local control rate at10-year was obtained 98% in non-secreting
adenoma which was superior to each type of secreting adenomas
 Acrommegary: 85%
 Prolactinoma: 83%,
 Cushing disease: 67%).
 Age is the significant prognostic factors (p<0.05).

Follow Up
 Patients treated with radiotherapy need to be
followed for life
 To see response to treatment with serial hormone
estimation and MRI
 To detect and correct hypopituitarism 20 to Radiation
 Ophthalmologic follow up is indicated for who
presents with visual defects

Conclusions
 Surgery is initial TOC for all pituitary adenoma
except prolactinoma .
 Prolactinoma mainly medical therapy
 Post operative Radiotherapy reduces
recurrence, hyper secretion.
 Conventional external Radiotherapy and
SRS/SRT

Pituitary adenoma

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