Pitutary tumors and management

Pituitary Tumors

Dr. Romi Grover

Anatomy

• Hypophysis cerebri.• Ovoid body situated in the hypophysial fossa

of the sphenoid bone known as sella turcica.• Weight : 0.8 gm.• Size : 1.3x1x0.5 cm.

Embryology

• Entirely ectodermal in origin– Adenohypophysis

• Develops from Rathke’s pouch

• Upward invagination– Neurohypophysis

• Develops from the infundibulum

• Downward extension of the floor of the diencephalon

Parts

On embryological basis: Adenohypophysis (80%)• Pars infundibularis• Pars intermedia• Pars distalisNeurohypophysis (20%)• Median eminence• Infundibular stem• Infundibular process

• Adenohypophysis : superior Hypophysial artery: hypophyseal portal system

• Neurohypophysis : inferior hypophyseal artery.

• Hence, Dual circulation.o Arteries & veins o Portal venous system

Relations

Physiology Anterior lobe • Somatotrophs [50%]: acidophilic, GH.• Lactotrophs : acidophilic, Prolactin.• Corticotrophs : Basophilic, ACTH, pro-

opiomelanocortin, MSH, endorphins & lipotropin.• Thyrotrophs : TSH.• Gonadotrophs : Basophilic, FSH-LH. Posterior lobe • Oxytocin.• ADH.

Epidemiology • Pituitary tumors are relatively uncommon • Comprising 10-12% of all intracranial tumors.

• Up to 22% of normal pituitary gland show adenoma at the time of autopsy • Most tumour present with in 30- 50 yrs

• 3-7 % under the age of 20 years

Etiology • Unknown • Genetic factors

MEN-1 syndrome Autosomal dominant syndrome

characterize by the development of tumour of pituitary, parathyroid, pancreatic islets cell

Three% of all tumour arise as a results of MEN 1 PA develops in 25 %patients with MEN-1

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

• Based on radiological findings. – Microadenomas (i.e., the greatest diameter is <10 mm) corticotrophs, lactotrophs. – Macroadenomas (i.e., the greatest diameter is ≥I0 mm). functioning & Non- functioning.

• Most pituitary adenomas are microadenomas.

• Functional criteria- which are used to define tumors in terms of their endocrine activity in vivo.– Functional [ acidophilic /basophilic]– Nonfunctional : [chromophobic]

Clinical presentationHormone Signs and

symptoms of hypersecretion

Signs and symptoms of hyposecretion

Lab Values

FSH, LH Clinically silent Mood swings, impotence, vaginal dryness, hot flashes, osteoporosis, decreased libido

LH, FSH, Serum testosterone, Serum estradiol

ACTH Cushing’s disease-moon facies, buffalo hump, puple striae, hypertension

Weight loss, nausia, hyponatremia and hypoglycemia, hypotension, fatigue

Serum cortisol

TSH Goiter, moist skin, tachycardia, palpitations, insomnia

Weight gain, fatigue, constipation, cold intolerance, bradycardia

TSH, free T4

Hormone Signs and symptoms of hypersecretion

Signs and symptoms of hyposecretion

Lab Values

Prolactin Menstrual irregularites, infertility, galactorrhea, weight gain

Silent Prolactin

GH Acromegaly-overgrowth, carpal tunnel, hyperhidrosis

Dwarfism, fatigue, osteoporosis, weight gain

IGF-1, GH

• Posterior gland (Neurohypophysis)– Oxytocin• Uterine contractions and lactation

– Anti-diuretic hormone• SIADH-increased water resorption, low sodium• DI-increased urination, high sodium

Disorders associated with the adjacent compression

• Lateral: Cavernous sinuses : diplopia, opthalmoplegia, ptosis, diminished corneal sensation, or facial paresthesias in the upper face.

• Superior: optic chiasm & hypothalamus.• Inferior: sphenoid sinus.

• Pitutary Apoplexy : • severe headache• altered consciousness• opthalmoplegia• blindness.• severe hypopituitarism • Medical emergency : administration of stress

doses of steroids, fluid , and pain control. Urgent surgery is also generally warranted to avoid potential permanent sequelae.

Types of Adenomas

• Prolactinomas : 40% to 45% of all pituitary tumors.

• Women > men.• Clinical presentation: Oligo/amenorrhea, galactorrhea, infertility &

androgenization with hirsutism & acne in women.

Reduced sexual function and libido in men.

• Acromegaly : GH hypersecretion • Source somatotroph adenoma Ectopic GH/GHRH.• Insidious nature – delayed diagnosis- macro adenomas

at detection.• Growth of hands and feet. • Jaw growth and prognathism • Hypertrophic cardiomyopathy.• Sleep apnea syndrome• Arthropathy, colon polyps• Carpal tunnel syndrome• Headache.

• Cushing's Disease : overproduction of glucocorticoids .• Obesity• Diabetes mellitus• Hypertension• Muscle wasting• Osteoporosis• Depression• Coagulopathy• cognitive deficits.• the 5-year cardiovascular mortality for untreated

disease is 50%

• Nonfunctioning Pituitary Adenomas : • Detected incidentally• Workup of visual field loss, headache, modest

hyperprolactinemia (from compression of the hypophyseal stalk), or hypopituitarism.

Evaluation • History and physical examination with detailed

neurological examination.• Comprehensive endocrine evaluation. S. Prolactin [ > 200ng/ml] Basal GH, IGF-1, glucose suppression, insulin

tolerence, TRH stimulation S.ACTH, 24 Hr Urine for 17 OH corticosteroids,

dexamethasone supression test.ACTH from B/L inf. Petrosal sinuses.TSH,T3, T4.FSH, LH, testosterone levels, estradiol levels.

• CEMRI brain.• Neuro-opthalmologic examination with visual

field tests.• Skeletal survey : acromegaly.

Hardy & Vezina Staging System• Gr I: normal sized sella with possible

asymmetry of the floor. • Gr II: Enlarged sella with an intact floor.• Gr III: Localized erosion or destruction of the

sellar floor.• Gr IV: Diffusely eroded or destroyed floor. Gr-I & G II – enclosed adenomas. Gr-III & Gr IV – invasive adenomas.

• Therapeutic goals of Pituitary adenomas Pituitary Adenomas• Eliminate mass effect and reverse related signs

and symptoms• Normalize hormone hyper secretion and reverse

secondary effects• Preserve or recover normal pituitary function• Prevent recurrence• Increase survival• Improve quality of life

Management

• Medical• Surgical• Radiotherapy

Medical Prolactinomas : • Dopamine agonists : Bromocriptine and

cabergoline. 80-90% . GH adenomas:• Somatostatin analogs : octreotide, lanreotide.• Dopamine agonists: less effective.• GH receptor antagonist: pegvisomant : daily inj. Cushing disease: • ACTH synthesis/release: cyproheptadine,

bromocriptine, somatostatin, and valproic acid.

• Steroid Synthesis Inhibitor: Ketoconazole, mitotane, trilostane, aminoglutethimide and metyrapone.

Surgery

Indications: • Rapidly progressive vision loss.• Increase in adenoma size despite dopamine

agonists.• Intolerance or inadequate hormonal response

to medical therapy. All symptomatic Pituitary adenomas TOC is Resection Transsphenoidal Transcranial

Advantages : • Hormone levels normalize in 1-12 weeks.• Mass effects can be decompressed quickly • Endocrine hypersecretion decreased or

eliminated• Existing pituitary function retained or improved

rapidly Disadvantages: • Recurrence rate is relatively high with surgery

alone. B/L adrenalectomy: life long glucocorticoids.

Surgical Cure Rate

• Prolactinomas microadenomas-50-60% macroadenomas-25%.• GH adenomas : microadenoams- 68%• macroadenomas-54% • Cushing syndrome : 57-90%.

Radiation Therapy Indications : • Residual surgical tumors• Medically inoperable tumors.• Effective for controlling pitutary adenoma

growth & progression. BUT less effective in normalizing hormonal activity. 10 RT: Medically Inoperable. refusal to surgery.

Radiation Techniques

• Conventional Radiotherapy.• 3D-CRT• IMRT• Radiosurgery Gamma knife. Cyber knife.• Proton Therapy.

Conventional • Position - supine • Head and neck flexed• Head typically held at 450 .• 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

3D CRT

• CECT scan should be obtained.• When possible, CE MRI should be registered

to the planning CT scan.• Normal structures to be contoured including

the eyes (lenses), optic nerves, optic chiasm, brainstem, and temporal lobes.

Target volumes• GTV : pituitary adenoma, including any extension

into adjacent anatomic regions. • CTV: limited to a 5-mm margin around the tumor is

adequate. With invasive tumors, Often, the entire

contents of the sella and, if appropriate, the entire cavernous sinus are included in the CTV.

• PTV : 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.

• Typically 5x5 cm field used, centered on sella

XRT Dose Bio. control 1.8Gy/#

Nonfunctioning 45-50.4 Gy 95% NA

Functioning 50- 54 Gy 90-95% 33-95%

Correlation of vision improvement, tumour control with dose of radiation

therapy in 121 patients treated with surgery and XRT Dose (Gy) <30 30-39.99 40-49.99 50-54 >54 p value

% with improved visual status 14 29 42 70 0 0.003

% failure 71 25 15 6 0 <0.01

Gringsby et al. Int J Radiat Oncol Biol Phys 1989 ;16:1411

SRS• Dose : 10-27 Gy• Cranial hard fixation tech• Adverse CNS event : 38%• ? Higher response rate.

FSRT• Conventional doses: 45-50 Gy• Using re-locatable head frame tech• Adverse CNS event : 0%

• Advantages

– Rapid dose fall off outside the target volume– Conformality of prescribed dose to the target volume– Radiosurgery may provide a more rapid radiographic

and hormonal response than fractionated radiation therapy

• 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 optic apparatus

– Size > 3 cm

Proton Therapy • 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

• Energy -either 155 or 200 MeV depending on the required beam penetration.

• PTV - all gross visible tumor (or all intrasellar contents with micro adenomas) with a 5-mm margin.

• The most common arrangement included 4 fields.

Disadvantages: • High cost of installation• Limited utility in other malignancy

Late effects • Late optic neuritis [0.7- 2%]• 2nd Malignant neoplasms. Royan Marsden 1.3% at 10yrs. Hospital with

1.9% at 20yrs. 45Gy. • Radiation Necrosis .• Hypopituitarism [10-30%] Surgery alone carries lower risk than RT Radiotherapy alone has lower risk than when RT

and surgery combined

Criteria for cure

• Tumor type Criteria Acromegaly Normalization of IGF-1 levels Random GH<2.5 ng/ml

GH<1 ng/ml (OGTT)

• PRL PRL< 20 ng/ml

• Cushing’s disease Normal 24 hour UFC

Conclusion • Small organ but critical functions for normal

development, growth, organ regulation, reproductive regulation, birthing functions.

• Dysfunction – endocrine abnormalities & mass effects.

• Chronic hypopituitarism – mortality due to cardiovascular events.

• Cumulative role of medical management & radiotherapy.

• No change in the quality of life when hormone deficiencies are suitably replaced.

Thank you