pituitary tumors. account for 10-25 % of brain tumors medium age at debut: between 20-50 years...
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PITUITARY TUMORS
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• 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
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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
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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
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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
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Pituitary macroadenoma
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Microadenoma
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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
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Effects of pituitary enlargement on optic chiasma and visual field
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Loss of lateral visual field due to optic chiasm compression
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Nerve IV palsy
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Radiological signs in pituitary macroadenoma: enlarged sella turcica, destroyed sellar walls
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CT
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MRI – Pituitary adenoma T1 imaging
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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
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MRI Imaging – invasive macroadenoma
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Invasive macroadenoma with temporal extension
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TREATMENT of PITUITARY ADENOMAS
• SURGERY
• RADIOTHERAPY
• PHARMACOTHERAPY
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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
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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
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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
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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
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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
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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
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Gamma knife irradiation
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Effect of gamma knife irradiation in a pituitary adenoma
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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.
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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”
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Microprolactinoma Macroprolactinoma
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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
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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
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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
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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
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Large prolactinoma cured by dopamine agonists
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ACROMEGALY
PREVALENCE:• 40 – 60 cases / 1 milion /year
• 3-2 new cases per year
• 1 / 15.000 person
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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,
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Histology of a acidophilic GH secreting adenoma
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Development of the disease is insidious and graduated during years, the disease being recognized 10 years after real debut
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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
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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
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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
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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
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Hand of an acromegalic patient.
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Enlarge feet.
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Anchor-like shape of the diastal phalange in acromegaly
Normal
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Increased thickness of heel soft tissue
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ACROMEGALY – metabolic problems
• Lypolisis• Insulinoresistence• Diabetes mellitus• Hypercalciuria, hypercalciuria• Sodium and water retention
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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
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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
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OCTREOSCAN – Indium labeled Somatostatin scintigraphy allows to detect somatostatin
receptors and predicts the response of tumors to somatostatin analoques
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Pancreatic tumor producing GH-RH with pituitary hyprplasia , excessive GH secretion and
acromegaly
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ACROMEGALY TREATMENT
• Surgery: transphenoidal, transcranial• Radioterapy• Long-acting somatostain analoques• Inhibitors of GH receptor
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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
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ACROMEGALY pharmacotherapy
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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
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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
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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
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Prolactinoma
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