PITUITARY TUMORS

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

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

HISTOGENESIS OF PITUITARY TUMORS

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

HISTOGENESIS OF PITUITARY TUMORS

Another pathogenic hypothesis is an activating mutation of alpha subunit of GTP-binding protein which activates cAMP and stimulates cell proliferation

În 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– Exophtalmos : 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

DIAGNOSIS OF PITUITARY ADENOMAS

• 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

TREATMENT of PITUITARY ADENOMAS

• SURGERY

• RADIOTHERAPY

• PHARMACOTHERAPY

SURGICAL TREATMENT OF PITUITARY ADENOMAS

• 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

SURGICAL TREATMENT OF PITUITARY ADENOMAS

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

SURGICAL TREATMENT OF PITUITARY ADENOMAS

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

SURGICAL TREATMENT OF PITUITARY ADENOMAS

Complication 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

IRRADIATION IN PITUITARY ADENOMAS

Convenţional 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

Succes:• 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

IRRADIATION IN PITUITARY ADENOMASComplications 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 yearsOnly 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 and 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 and hyperprolactinemiaIn 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

OTHER CAUSES OF HYPERPROLACTINEMIA

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

• Interruption of conection 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, l-DOPA, 5HT2 inhibitors, estrogeni, oral contraceptives

• Hypothalamic diseases: sarcoidosis, hysticytosis• Polycystic ovarian disease, acromegaly, hipothyroidism,

kidney failure, liver cirrhosis• Torax unjuries

ASSESSEMENT OH HYPERPROLACTINEMIA

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

• Assessement of lesions: CT, IRM

TREATMENT OF PROLACTINOMAS

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– Cabergolină: 0,5 – 3,5 mg /week– quinagolid

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

TREATMENT OF PROLACTINOMAS

SSurgery• 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

C. 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 and 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 IGF1 excess produce

– Hypertrophy of all structures containig connective tissue and bone

– Metabolic abnormalities

ACROMEGALY SIGNS AND SYMPTOMS

SIGNS AND SYMPTOMS AT THE DEBUT:• Headache• Joint and bone pain• Dental problems• Amenorhea, galactorhea, loss of libido• Diabetes mellitus• Hyperhydrosis• Carpal tunell syndrome• Sleep apnea• HTA, cardiomyopathy• Colonic poliposis

ACROMEGALY signs and symptoms

• Pituitary tumor syndrome: • Narrowing of the visual field, • Decreased visual acuity

• Facial abnormalities: – Prominent frontal boses– Prominent occipital bone– Enlargement of low jaw – Dental : spaces between tees– Large tongue

ACROMEGALIA signs and symtpoms

• Abnormalities of hands and feet: – Thicknening of the fingers– Carpal tunell syndrome

• Joints and spine: – Spondilosis– Osteoarthritis– skin: hyperhidrosis– Cutis giratta– Moluscum pendulum– Skin spots

Hand of an acromegalic patient.

Enlarge feet.

Anchor-like shape of the diastal phalange in acromegaly

Normal

Increased thickness of heel soft tissue

ACROMEGALY – metabolic problems

• Lypolisis• Insulinoresistence• Diabetes mellitus• Hypercalciuria, hypercalciuria• Sodium and water retention

ACROMEGALy – Complication

• Hearth :– Increased cardiac volume and systolic volume– Interstitial fibrosis– Systolic and dyastolic dysfunction– Ventricular dillatation– Hearth failure

• Lung:– Laringeal hypertrophy– Respiratory dysfunction – Sleep apnea

• Digestive : colonic polyposis• Other tumors

ACROMEGALIA – diagnosticGH increased in multiple

determinations. IGF-1 increased

GH during OTTG

GH below < 1 ng/ml GH not inhibited during OTTG

Imagery CT, IRM

Fundus of the eye VF

Nu este acromegalie

OCTREOSCAN – Indium labeled Somatostatin scintigraphy allows to detect somatostatin

receptors and predicts the response of tumors to somatostatin analoques

Pancreatic tumor producing GH-RH with pituitary hyprplasia , excessive GH secretion and

acromegaly

ACROMEGALY TREATMENT

• Surgery: transphenoidal, transcranial• Radioterapy• Long-acting somatostain analoques• 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 les than 2.5 ng/mL

• Normal IGF

ACROMEGALY pharmacotherapy

ACROMEGALIA TRATAMENT MEDICALDrugs Debut dosage

Maximal dosage

Side effects Monitoring

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

Octreotide LAR Long acting

somatostatin analoque

20 mg/ month

30mg/ month nausdea

colethiasisGH, IGF1

US

LanreotidLong acting somatostatin analoque

30 mg/ x2 4week

30 mg/x4/ week

The same Same+ MRI anually

Lanreotid autogel

60 mg/ 4 week

120 mg/ 4 week

The same Same+ MRI anually

Pegvisomant 10 mg/ zi s.c.

40 mg/zi s.c. Headache, lethargy, increased of tumor volume if not associated with somatostatin analoques

MRI anualyLiver enzymes

ACROMEGALY: pharmacotherapy

Treatment of complications

• Osteoarthritis• Osteoporosis• Hypercalciuria• Hyperparatiroidism in MEN1• Treatment of sleep apnea• Monitorig Hb A1c, 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, Dexametasone inhibition test, • Tretament: surgery and /or gamma knife

Prolactinoma