PITUITARY TUMORS

pituitary gland is a midline structure

measuring approximately 15 mm in AP and 12 mm in the SI axis.

The pituitary gland occupies a cavity of the sphenoid bone, called the sella turcica

The diaphragm sellae, an extension of the dura, separates the pituitary gland from the structures lying above it

ANATOMY

ANATOMY

The diaphragm sellae is traversed by the pituitary stalk

connects the median eminence of the pituitary to the hypothalamus.

The posterior border of the sella is formed by the dorsum sellae

thin structure with two prominences: the posterior clinoids.

The tuberculum sellae lies anteriorly in the floor of the sella turcica, and projects laterally as the anterior clinoid processes.

Lateral to the sella are the cavernous sinuses

The pituitary gland has two components of distinct embryologic origins.

The anterior and intermediate lobes of the pituitary gland arise from Rathke's pouch

an evagination of ectodermal tissue from the roof of the oral cavity

The posterior lobe (or neurohypophysis) and stalk arise from a down-pocketing of the third ventricle.

The posterior lobe contains terminal axons from neurons originating in the hypothalamus.

Secretory granules are synthesized in the supraoptic and paraventricular nuclei and transported along the stalk to the posterior lobe

where they are released as the posterior pituitary hormones oxytocin and vasopressin

Secretion of anterior pituitary hormones is controlled by hypothalamic hormones carried by the hypothalamic-hypophyseal portal system

corticotropin-releasing hormone thyrotropin-releasing hormone GH-releasing hormone GH-inhibiting hormone or somatostatin FSH-releasing hormone LH-releasing hormone prolactin-releasing hormone prolactin-inhibiting hormone

ANTERIOR PITUITARY HORMONES

Adrenocorticotropic hormone (ACTH)

thyroid-stimulating hormone (TSH)

growth hormone (GH)

follicle-stimulating hormone (FSH)

luteinizing hormone (LH)

prolactin

10% of the healthy adult population has pituitary abnormalities detectable by MRI

Pituitary neoplasms account for 10% to 15% of diagnosed primary intracranial neoplasms

Approximately 70% are endocrinologically active

The incidence of macroadenomas is similar between males and females

Epidemiology

clinical manifestations of microadenomas are more frequent in women.

Seventy percent of adenomas present between the ages of 30 and 50

The etiology of most pituitary adenomas is unknown.

A genetic predisposition

25% of patients with MEN type-1

the Carney complex -inherited condition with spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas

isolated familial somatotropinomas (IFS) -occurrence of two or more cases of acromegaly in a family in the absence of MEN or the Carney complex

ETIOLOGY

Most of the pituitary adenomas arise from the anterior lobe, are benign in nature.

Pituitary adenoma can be categorized

secretory or nonsecretory tumors (ratio of 2:1)

Tumors that hypersecrets- prolactin, corticosteroids, and GH account for 50, 25, and 20%

Depending on size (Jules Hardy classification)

microadenomas (tumor diameter less than or equal to 10 mm)

macroadenomas (tumor diameter greater than 10 mm).

Corticotroph and lactotroph adenomas tend to be microadenomas

other functional and the nonfunctioning adenomas are usually macroadenomas at diagnosis

Clinical feature

local tumor extension (mass effect and neuro-ophthalmic manifestation)

hormonal dysfunction (endocrine syndromes)

Due to local extension

Common symptoms: headache, extraocular palsies, and visual symptoms

Extension laterally into the cavernous sinuses

cause diplopia, opthalmoplegia, ptosis, diminished corneal sensation, or facial paresthesias in the upper face

If extension occurs superiorly the optic chiasm

bitemporal hemianopic and superior temporal deficits, homonymous hemianopsia, central scotoma, and inferior temporal field defects

inferior growth causes extension into the sphenoid sinus

Hypopituitarism - compression of the native pituitary gland and resulting hyposecretion of pituitary hormones

Large tumors that are allowed to grow unabated can ultimately extend into the temporal lobe, third ventricle, and posterior fossa.

Clinical Manifestations of Hormonal Excess

Pituitary apoplexy,-acute infarction and hemorrhage of a pituitary adenoma.

Apoplexy usually occurs in macroadenomas

C/F- severe headache, altered consciousness, opthalmoplegia, and visual deficits including blindness.

Imaging studies usually reveal intratumoral hemorrhage (sometimes ischemic changes).

These patients present with severe hypopituitarism

require urgent medical care for administration of stress doses of steroids, fluid administration, and pain control.

Urgent surgery is also generally warranted to avoid potential permanent sequelae.

PATHOLOGY

With classic fixation, staining, and light microscopy

pituitary tumors are designated as

Chromophobic

Basophilic

acidophilic

Acidophilic tumors were thought to be associated with acromegaly

basophilic tumors with Cushing's disease

chromophobic tumors with nonfunctional

But these properties may not correlate with clinical or immunohistochemical findings

Newer methods of fixation and staining, electron microscopy, and immunohistochemical procedures can identify cells secreting GH, ACTH, TSH, and prolactin

Hormonally inactive adenomas referred to as null cell adenomas

now often pathologically classified as members of the gonadotroph family.

Evaluation

MRI gadolinium enhancement test of choice

High degree of sensitivity for micro & macro adenoma

Micro- hypointense Macro- isodense in unenhanced T 1 wtd

image Macro adenoma – compression of adj

pituitary & may distort stalk, larger – extrasellar extn

Imaging

Goals

remove or control tumor masses

control hypersecretion

correct endocrine deficiencies

while minimizing the risk of hypopituitarism or injury to adjacent structure

Management

MANAGEMENT OPTIONS

OBSERVATION

MEDICAL THERAPY

SURGERY

RADIOTHERAPY

Observation -an option for nonsecreting microadenomas

small asymptomatic prolactinomas

imaging must be performed at least yearly for the duration of the patient's life

When you will intervene?

Tumor growth on imaging

symptoms of hypersecretion

development of visual field deficits

Comorbidities associated with alterations in hormonal levels including

Hypertension

Osteopenia

Diabetes

electrolyte imbalance

Dyslipidemia

increased mortality rates seen in acromegaly

Excess circulating levels of GH and IGF-I

multiple metabolic disturbances, cardiovascular and respiratory comorbidities

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.

Transsphenoidal microsurgery

Mortality rate of approximately 0.5%

Major complications

Meningitis Cerebrospinal fluid leak Hemorrhage Stroke Visual loss

Approximately 1.5% of the procedures.

Contraindications

sphenoid sinusitis

ectatic midline carotid arteries

significant lateral suprasellar extent

A transcranial approach is preferred in such situations

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

by 10 years after radiation therapy, 60% to 100% of patients have GH levels <10 ng/mL

following failure of local therapies

while awaiting the typically slow response to radiation.

Pharmacological therapy

Agents used

somatostatin analogs (octreotide and lanreotide)

reduce GH and IGF-I levels in 50% to 60% of patients who have failed surgery

Tumor shrinkage occurs in 30% to 45% of patients

A/E-transient abdominal cramps malabsorptive diarrhea, nausea of mild-to-moderate intensity Gallbladder sludge or stones may develop in 15%

dopamine agonists

GH receptor antagonist- Pegvisomant, a genetically engineered GH receptor antagonist

effective in reducing serum IGF-I concentrations

Daily injections of pegvisomant resulted in normalization of IGF-I in 89% of patients

A/E-diarrhea, nausea, flu syndrome, and abnormal liver function tests

Management scheme for growth hormone (GH)-secreting macroadenomas

Observation

Surgery

Medical therapy

radiotherapy

Prolactin-Secreting Adenomas

A dopamine agonist-

Bromocriptine and cabergoline

Bromocriptine results in rapid normalization of prolactin levels in 80% to 90% of patients

Bromocriptine can also reduce tumor size in about 80% of cases, although size reduction can be modest

Medical Therapy

Long-term therapy appears to be required

The dose may be reduced considerably once a response is obtained

Complete discontinuation of bromocriptine results in recurrent hyperprolactinemia in 80% to 90% of patients

A/E -transient nausea and vomiting

Orthostatic hypotension may also occur at the initiation of therapy

Cabergoline is as effective as bromocriptine in lowering prolactin levels and reducing tumor size

And has a better toxicity profile

Biochemical recurrence rates 2 to 5 years after withdrawal were 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

Patients with large tumors (>2 cm in diameter)

prolactin levels above 20 ng/mL typically fare worse

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

Radiation Therapy

Patients receiving dopamine agonists at the time of radiosurgical treatment had a significantly worse outcome

A 2-month break between medical therapy and radiotherapy was suggested

Management scheme for prolactin-secreting macroadenomas

Surgical Management-

Selective transsphenoidal removal of the ACTH-secreting adenoma remains the standard of care

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%

Cushing's Disease

Bilateral adrenalectomy is reserved for patients who have failed other treatment modalities

The procedure can performed laparoscopically

induces a predictable and rapid hormonal response

patients subsequently require lifelong treatment with glucocorticoids and mineralocorticoids

Bilateral adrenalectomy can also result in Nelson's 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

Radiation Therapy

Forty-nine percent of patients normalized their cortisol level at a median of 7.5 months following radiosurgery (Devin et al)

a trend for late recurrences in up to 20% of patients treated with radiosurgery

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

Management scheme for adrenocorticotropic hormone (ACTH)-secreting macroadenomas

first directed toward relief of any mass effect

If the tumor cannot be resected completely, decompression of the chiasm (if indicated)

followed by radiation provides excellent long-term results

use of adjuvant radiotherapy significantly reduces local recurrence

Nonfunctioning Pituitary Tumors

risk factors for recurrence

local invasion

suprasellar extent

residual tumor on postoperative imaging

recurrences continue to occur 10 to 20 years following surgery- MRI-confirmed complete resection

Image-based treatment planning using a three-dimensional technique is the standard of care

All diagnostic evidence, but particularly MRI and CT, as well as clinical and surgical findings, should be used to define the tumor volume.

Registration of a contrast-enhanced MRI scan with the treatment CT scan allows for optimum definition of the tumor and the optic apparatus

Radiation Therapy Techniques

(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.

Standard thermoplastic masks are associated with setup variability of the order of 3 to 4 mm.

A total PTV margin of 5 mm is usually reasonable

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

Immobilization will generally be performed with a thermoplastic mask

For three-dimensional simulation, a contrast-enhanced planning CT scan is obtained.

When possible, a thin- slice T1-weighted contrast-enhanced MRI should be registered to the planning CT scan.

The volumes described are then defined on the MRI but reviewed on the CT.

Normal structures to be contoured include the eyes (lenses), optic nerves, optic chiasm, brainstem, and temporal lobes.

Beam arrangements

The use of two lateral opposed portals should be avoided in order to decrease the dose to the temporal lobes.

A simple technique is to use three static shaped beams: wedged opposed laterals and an anterior or vertex beam that enters above the eyes

When complex treatment planning is available

five noncoplanar beams present a good solution.

This allows custom beam shaping and optimal normal structure sparing.

The beams are hemispherically distributed, avoiding entry or exit through the eyes

Photons in the megavoltage range should be used to spare surrounding structures, most notably the temporal lobes.

Six- to 10-MV photons are generally used.

Pituitary adenomas show dose-response rates that depend on tumor type

Nonfunctioning 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

contraindicated if the optic chiasm is closer than 3 to 5 mm to the tumor

After fixation of the appropriate stereotactic head frame, a high-resolution imaging study is obtained.

the dose to the optic chiasm must be kept <8 to 9 Gy

The dose prescribed will be 12 to 20 Gy for nonfunctioning tumors

15 to 30 Gy for functioning adenomas

Radiosurgery

The acute complications

Fatigue

focal alopecia

otitis

Sequelae of Treatment

Long term complications include

Hypopituitarism (25-80% with conventional RT and 5-40% radiosurgery)

Impairment of vision (1-2%)

Second malignancy -The cumulative risk of second brain tumors (mainly meningiomas and high-grade astrocytomas) was 2.4% at 20 years

Brain necrosis < 1%

Contrast-enhanced MRI is the imaging modality of choice

It should be obtained at least yearly

Monitoring of hormonal response

Both insulin growth factor-I (somatomedin-C or IGF-I) and GH levels should be followed in acromegaly

Posttherapy Evaluations

In prolactin-secreting tumors-measurement of plasma and urine steroids and plasma ACTH levels.

Periodic assessment of gonadal, thyroid, and adrenal function is necessary.

regular formal visual field testing should be performed following radiotherapy.