PITUITARY TUMOURS – AN OVERVIEW

DR.RAVIRAJ GHORPADE
CONSULTANT BRAIN & SPINE SURGEON
BELGAUM
 Introduction
• Pituitary (hypophysis cerebri) - master of endocrine orchestra
• Occupies a cavity of the sphenoid bone (sella turcica)
• Roof is formed by diaphragm sellae
• The stalk of pituitary is attached above to the floor of 3rd ventricle
• Anterior lobe releases hormones ACTH, TSH, GH, FSH, LH, Prolactin
• Posterior lobe releases hormones oxytocin and vasopressin
 PITUITARY TUMORS
• Account for 10-25 % of brain tumors
• Medium age at debut: between 20-50 years
• Children rarely have pituitary adenomas. Most tumor in children are
craniphariogiomas and are associated with growth failure and diabetes insipidus.
• Most pituitary adenomas in children are prolactinomas
• Prolactinomas, Gh secreting adenomas and ACTH-secreting adenomas are more
frequent in women. GH secreting adenomas are more frequent in men.
 PITUITARY TUMORS - CLASSIFICATION
According to their size:
• Microadenomas: have less than 1 cm, do not modify the shape of sella turcica and
do not produce pituitary tumor syndrome
• Macroadenomas: have nore tahn 1 cm. and according to the direction they develop
produce “the syndrome of pituitary tumors”

According to their degree of aggression

• Benign adenomas
• Invasive adenomas
• Carcinamas: less then 1 % of pituitary tumors
 PITUITARY TUMORS: HISTOGENESIS

Two hit hypothesis:

• Pituitary adenomas are monoclonal tumors
• Polyclonal adenomas may result from excessive stimulation of
pituitary by specific releasing hormones
• Pituitary cells have a genetic protective factor against tumor
proliferation. Lost of one protective allelle - first hit is not
associated with tumor transformation, a point mutation of the
second allelle – second hit results in tumor proliferation . Tumor
occurs only if both protective factors are lost
 PITUITARY TUMORS: HISTOGENESIS
• Another pathogenic hypothesis is an activating mutation of alpha subunit of
GTP-binding protein which activates cAMP and stimulates cell proliferation

• In MEN 1 – Multiple Endocrine Neoplasia type 1 there is an autosomal

dominant deletion of a protective gene MENINE encoded on chromosome 11
(11q13) and multiple tumors simultaneous or successive occur:
- multiple parathyroid adenoams with primary hyperparathyroidism
- gastro-entero-pancreatic tumors: gastrinoma, insulinoma, glucagonoma
- carcinoid tumors
- adrenal adenomas
- lipomas
- facial angiofibromas
Pituitary macroadenoma
Microadenoma
 PITUITARY TUMOR SYNDROME

• NEUROLOGIC SYMPTOMS:
– Headache
– Nerves III, IV and VI which cross the cavernous sinus
– Temporal seizures
– Other seizures
– Meningeal signs
• OPHTALMOLOGIC SIGNS
– Decreased visual acuity
– Reduction of visual field according to tumor extension
– Exophthalmos: rare
• RADIOLOGICAL SYGNS
– Enlarged surface of sella turcica
– Radiologic signs specific for some pituitary adenomas: acromegaly
Effects of pituitary enlargement on optic chiasma and visual field
Loss of lateral visual field due to optic
chiasm compression
Nerve IV palsy
Radiological signs in pituitary macroadenoma: enlarged sella turcica, destroyed
sellar walls
CT
MRI – Pituitary adenoma T1 imaging
 PITUITARY ADENOMAS: DIAGNOSIS

• Clinical suspicion
• Assessment of pituitary hormones to determine hormonal
secretion of adenomas and level of other pituitary hormones in
case if pituitary is partially dystroyed.
• Radiograph of sella turcica: useful in case of macroadenomas
• CT or MRI of hypothalamic-pituitary area
• Inhibitory tests, biochemical markers for some adenomas
MRI Imaging – invasive macroadenoma
Invasive macroadenoma with temporal extension
PITUITARY ADENOMAS: TREATMENT MODALITIES

• SURGERY
• RADIOTHERAPY
• PHARMACOTHERAPY
 PITUITARY ADENOMAS: SURGICAL TREATMENT

• First intention therapy for all adenomas with exception of those

which have a proven beneficial pharmacological treatment
• Immediately indicated in tumors which exert compression over
structures from the proximity and involve a risk for sight loss or have
intracranial hypertension.
• Is an emergency treatment for pituitary apoplexy – pituitary infarct.
• May be delayed until pharmacological treatment may reduce tumor
volume and make the tumor more accessible to surgery in some
responsive cases
 PITUITARY ADENOMAS: SURGICAL TREATMENT

Aim of surgery:
a. To reduce mass effect produced by large tumors over
adiacent structures
b. To inhibit hormone secretion in pituitary secreting
adenomas
c. To preserve morphologic and functional integrity of the
pituitary
 PITUITARY ADENOMAS: SURGICAL TREATMENT

Approach of the pituitary during surgery:

a. Transcranial approach: in large tumors with extra selar extension. The
aim is to reduce tumor volume and has greater number of
complications
b. Transphenoidal approach – is used in most adenomas with medium
and small size. This treatment have no complications in a skillful hand
and preserves the pituitary function if it was not previously affected.
• Complete cured: 90 % of microadenomas
• Tumor reduction without complete cure in larger tumors
 PITUITARY ADENOMAS: SURGICAL TREATMENT

• Complications of pituitary surgery depend of the size of the tumor and

quality of surgery:
• Death by carotid injury
• Severe complication due to injury of cavernosal sinus and nerves III,IV and VI
• Brain injuries
• Chiasma injury with complete sight loss
• Infections: meningitis, enchephalitis
• Cerebro-spinal flud fistula
• Diabetes insipidus: permanent 5 % of (frequently transitory condition – some
weeks)
• Syndrome of inapropriate vasopressine secretion 10 %
• Hypopituitarism 5-10 % in large tumors
 PITUITARY ADENOMAS: RADIATION THERAPY
Conventional irradiation:
The tumor is irradiated based on a computerized program which includes CT and
MRI in order to spare the proximal regions with CT/IRM 4000 – 5000 cGy, in
fractionated doses of 180 – 200 cGy per day, 5 days per week

Success:
• 80 % in acromegaly, but full effect appear variably in time until 8 years and even
more
• 55 – 60 % in ACTH-secreting tumors , in a shorter time
• In prolactinomas the response rate is less important because tumor secretion may
be successfully controlled with dopamine agonists
 PITUITARY ADENOMAS: RADIATION THERAPY
Complications of conventional irradiation:
• Hypopituitarism in 50-60 % of cases in 8-10 years
• Optic nerve injury
• Brain radio necrosis
• Occurrence of other neoplasia of the brain favor by previous irradiation

Gamma knife delivers in one MRI-guided the entire dose of irradiation on a very small
field
The effects of irradiation are more rapid – until 4 years
Only in tumors which are more distant of the optic chiasm: at least 4 mm
Until the cure obtained by irradiation the tumor secretion and growth must be
controlled by pharmacotherapy
Gamma knife irradiation
Effect of gamma knife irradiation in a pituitary
adenoma
 PROLACTINOMAS & HYPERPROLACTINEMIA

Prolactin excess inhibits gonadotropins secretion

In women:
•Secondary amenorrhea, oligomenorrhea,
infertility
•Galactorhea
•Hirsutism
•Signs of estrogen deficiency with genital atrophy
•Osteoporosis
•Pituitary failure in large prolactinomas
Most prolactinomas in women are microadenomas
 PROLACTINOMAS & HYPERPROLACTINEMIA

In men: decreased testosterone secretion with:

• Decreased libido
• Erectile dysfunction
• Infertility
• rare: gynecomastia şi galactorhea
• Pituitary failure

In men most prolactinomas are macroprolactinomas and are associated

with “pituitary tumor syndrome”
Microprolactinoma

Macroprolactinoma
 HYPERPROLACTINEMIA: OTHER CAUSES

• Physiological: breast feeding, sexual activity, sleep, stimulation of mammary gland

• Interruption of connection between hypothalamus and pituitary and inhibitory
control of the hypothalamus over pituitary, stalk section, stalk compression by other
tumors, hypothalamic tumors
• Empty sella syndrome
• Drugs which inhibit dopamine: psychotropes, antidepressives, levodopa, 5-HT2
inhibitors, estrogens, oral contraceptives
• Hypothalamic diseases: sarcoidosis, hysticytosis
• Polycystic ovarian disease, acromegaly, hypothyroidism, kidney failure, liver cirrhosis
• Thorax injuries
 HYPERPROLACTINEMIA: ASSESSEMENT

A. Prolactin values
• Prolactin levels correlates with tumor size
– Normal prolactin levels: 9-25 ng/ ml
– 50 ng/ ml functional hyperprolactinemia
– between 50-100 ng/ ml microprolactinomas
– over 100 ng/ ml macroprolactinomas
• Bromocriptine test:
– 2,5 mg bromocriptine must reduce prolactin levels
• Assessment of lesions: CT, IRM
 PROLACTINOMAS: TREATMENT

Pharmacotherapy – dopamine agonists

• First choice treatment in microprolactinomas and pre treatment in
macroprolactinomas in order to reduce tumor size and facilitate surgery
– Bromocriptine: 2.5-20 mg /day
– Cabergoline: 0.5-3.5 mg /week
– Quinagolid

• Effects of pharmacotherapy:
- menses resumes
- fertility is restored
- during pregnancy the treatment may be stoped
- during pregnancy the tumor is followed by assessing the visual field
 PROLACTINOMAS: TREATMENT

Surgery
• For large tumors with compressive symptoms
• May be done after previous pharmacotherapy
• Effects of surgery:
- in best cases gonadotropin secretion occurs again
- risks and complications are similar to other pituitary tumors submited to
surgery
- residual disease may be controlled with dopamine agonists
External irradiation is rarely needed
Large prolactinoma cured by dopamine agonists
 ACROMEGALY

PREVALENCE:
• 40 – 60 cases / 1 milion /year
• 3-2 new cases per year
• 1 / 15.000 person
 ACROMEGALY

Causes :
• sporadic:
– Adenoama pure high granulated, sparse granulate
– Mixed GH and prolactin secreting adenomas
– Acidofilic adenoams with stem cells
– Ectopic adenomas
– GH secreting carcinoma
– Mc Cune-Albright syndrome
• Familial forms: izolated, MEN 1, Carney complex, FIPA -
• Hypothalamic GH.RH excess: harmartoms, gangliocytoma, glyoma,
• Extrahypothalamic GH-RH secretion
– Pancreatic carcinoids, bronchial carcinoma MTC,
Histology of a acidophilic GH secreting adenoma
Development of the disease is insidious and graduated during
years, the disease being recognized 10 years after real debut
 ACROMEGALY – SIGNS & SYMPTOMS

• Signs and symptoms of the disease are determined by the effects of GH

and IGF1 over target tissues after the epiphyseal growth plates are
closed.
• In case of a precocious debut gigantism occurs
– Short and flat bones are more affected
– GH and IGF-1 excess produce
• Hypertrophy of all structures containing connective tissue and bone
• Metabolic abnormalities
 ACROMEGALY – SIGNS & SYMPTOMS

SIGNS AND SYMPTOMS IN THE BEGINNING:

• Headache
• Joint and bone pain
• Dental problems
• Amenorhea, galactorhea, loss of libido
• Diabetes mellitus
• Hyperhydrosis
• Carpal tunnel syndrome
• Sleep apnea
• HTA, cardiomyopathy
• Colonic polyposis
 ACROMEGALY – SIGNS & SYMPTOMS

• Pituitary tumor syndrome:

• Narrowing of the visual field,
• Decreased visual acuity

• Facial abnormalities:
– Prominent frontal bosses
– Prominent occipital bone
– Enlargement of lower jaw
– Dental: spaces between teeth
– Large tongue
 ACROMEGALY – SIGNS & SYMPTOMS
• Abnormalities of hands and feet:
– Thickening of the fingers
– Carpal tunnel syndrome
• Joints and spine:
– Spondilosis
– Osteoarthritis
– skin: hyperhidrosis
– Cutis giratta
– Moluscum pendulum
– Skin spots
Hand of an acromegalic patient.
Enlarged feet.
 Anchor-like shape of the distal
Normal phalange in acromegaly
Increased thickness of heel soft tissue
 ACROMEGALY – METABOLIC PROBLEMS

• Lypolisis
• Insulin-resistance
• Diabetes mellitus
• Hypercalcemia, hypercalciuria
• Sodium and water retention
 ACROMEGALY – COMPLICATIONS
• Heart:
– Increased cardiac volume and systolic volume
– Interstitial fibrosis
– Systolic and dyastolic dysfunction
– Ventricular dillatation
– Hearth failure
• Lung:
– Laringeal hypertrophy
– Respiratory dysfunction
– Sleep apnea
• GIT: colonic polyposis
• Other tumors
 ACROMEGALIA – diagnostic
GH increased in multiple
determinations. IGF-1 increased

GH during OTTG

GH below < 1 ng/ml GH not inhibited during

OTTG

Nu este Imagery CT, IRM

acromegalie Fundus of the eye VF
OCTREOSCAN – Indium-labeled Somatostatin scintigraphy allows to detect somatostatin
receptors and predicts the response of tumors to somatostatin analogues
Pancreatic tumor producing GH-RH with pituitary hyperplasia, excessive
GH secretion and acromegaly
 ACROMEGALY TREATMENT

• Surgery: transphenoidal, transcranial

• Radiotherapy
• Long-acting somatostatin analogues
• Inhibitors of GH receptor
 ACROMEGALY - SURGICAL TREATMENT

• In emergency if there are symptoms of pituitary apoplexy

• Guided by MRI and computer-assisted navigation
• Transphenoidal approach is most frequent

• Criteria for cure: GH during OTTG < 0.30 ng/ ml, partial response
medium GH per 24 h <2.5 ng/mL
• Normal IGF
 ACROMEGALY: PHARMACOTHERAPY
ACROMEGALIA TRATAMENT MEDICAL
Drugs Debut dosage Maximal dosage Side effects Monitoring

Cabergoline 1mg/7days 4mg/7 days Nausea GH, IGF1

Octreotide LAR 20 mg/ month 30mg/ month Nausea GH, IGF1

Long acting somatostatin cholelithiasis
analogue US
Lanreotid 30 mg/ x2 4week 30 mg/x4/ week The same Same+ MRI
Long acting somatostatin
analogue
anually
Lanreotid autogel 60 mg/ 4 week 120 mg/ 4 week The same Same+ MRI
annually
Pegvisomant 10 mg/ zi s.c. 40 mg/zi s.c. Headache, lethargy, MRI anualy
increased of tumor
volume if not associated Liver enzymes
with somatostatin
analogues
 TREATMENT OF COMPLICATIONS
• Osteoarthritis
• Osteoporosis
• Hypercalciuria
• Hyperparatiroidism in MEN1
• Treatment of sleep apnea
• Monitoring HbA1c, triglycerides
• Treatment of hearth complications
• Monitoring for colonic polyposis and colonic cancer
 ACTH- SECRETING ADENOMA

• Small or very small size

• Clinically manifested by Cushing’s disease
• Diagnosis: cortisol, dexamethasone inhibition test
• Tretament: surgery and /or gamma knife
 CONCLUSION
• Pituitary tumors are slow growing tumors
• Surgery is the first choice of treatment
• Radiation is generally used as an adjuvant or salvage therapy
• Surgery followed by post op radiation produce better results
• Newer treatment modalities like gamma knife produce less
complications
Questions?