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TUMORI HIPOFIZARE

Localizarea hipofizei

B: Empty sella: Partea anterioara a eii turceti este ocupata progresiv de un diverticul al
spaiului subarahnoidian, coninnd LCR

Sistemul port hipotalamo-hipofizar


Descoperirea anatomic a sistemului port
hipofizar n anul 1930 de ctre Gr.T. Popa i
Unna Fielding, i stabilirea rolului su
funcional de ctre G. Harris, elev al lui Gr. T.
Popa, a pus bazele Neuroendocrinologiei

Arterele hipofizare superioare, care dup ce se desprind din carotida intern se


capilarizeaz la nivelul eminenei mediane (regiunea hipotalamic unde se
termin tija hipofizar) i formeaz plexul capilar primar. Venele porte, cu
origine n plexul primar, coboar n lungul tijei hipofizare i se capilarizeaz a
doua oar la nivelul adenohipofizei, unde formeaz plexul capilar portal
secundar, din care sngele va fi drenat ctre sinusul cavernos.

TUMORILE HIPOFIZARE
Benigne (adenoame), rar maligne (numai in prezenta metastazelor)
Prevalenta: 10%-25% la autopsie
Incidenta: adenoame clinic manifeste: 1-2/100.000/an
Patogenie:
activarea oncogenelor:
- mutatie Gs alpha la 40% din tumorile GH-secretante
- PTTG: over-expressed in tumorile hipof
- mutatie Ras in tumori agresive(carcinoame)
- mutatie PRKAR1A in Carney syndrome
inactivarea unor gene supresor tumoral : MENI, AIP
alterari in expresia unor receptori si factori de crestere : FGF-2 &
ptd-FGFR4, EGF-R & ERBB2, NGF& p75NGFR activin, inhibin, follistatin, IL6,
LIF

reglatori ai ciclului celular : down-regulation of p16, p18, p27


over-expression of cyclin D1 and PTTG

Clasificarea tumorilor hipofizare

Marime: microadenom<1cm, macroadenoam>1cm


Coloratie: acidofile, basofile, cromofobe
Imunohistochimie:
Adenom secretant de GH/ PRL/ ACTH/ TSH/ FSH/ LH/
subunitati alfa; sau mixte ex. GH+PRL
Adenoame cu celule nule
Radiologic: clasificarea Hardy (incapsulate, invazive)

Manifestari clinice ale adenoamelor hipofizare

1. Manifestari datorate compresiei tumorale


2. Manifestari datorate excesului hormonal
3. Manifestari datorate hipopituitarismului
(insuficientei hipofizare)

ACROMEGALIA/ GIGANTISMUL
ADENOAME HIPOF. GH-SECRETANTE
(SOMATOTROPINOAME)

Manifestari clinice datorate secretiei GH


Simptome
Transpiratie excesiva (>80% din pacienti)
Cefalee
Oboseala, letargie
Dureri articulare
Cresterea nr. la picior, cresterea mainilor, extremitatilor

Semne
Faciale: trasaturi ingrosate, bose frontale, nas marit, prognatism, piele grasa,
largirea spatiilor interdentale
Ingrosarea vocii
Marirea limbii
Edeme ale tes. moi: sindrom tunel carpian
Modif. musculoscheletale: cresterea nr. la picior, cresterea mainilor,
osteoartrita, miopatie generalizata
Gusa si alte organomegalii (ingrosarea muc. bronsiolelor, hipertrofie
ventriculara)

COMPLICATII
1. HIPERTENSIUNE ARTERIALA (40%)
2. DIABET ZAHARAT(20%)/ TOLERANTA ALTERATA
LA GLUCOZA (40%)
3. APNEE DE SOMN OBSTRUCTIVA
4. BOALA CORONARIANA ISCHEMICA
/CEREBROVASCULARA
5. INSUFICIENTA CARDIACA CONGESTIVA
6. POLIPI COLONICI SI and CARCINOM COLONIC
7. COMPLICATII DATE DE MASA TUMORALA

INVESTIGATII
Test toleranta orala la glucoza
Lipsa de supresie a GH < 1ng/ml = acromegalie

IGF1 crescut pentru varsta si sex


TRH test numai la pacientii cu rezultate echivoce in OGTT

or IGF

La normali 200mcg TRH i.v. determina supresia GH.


La 80% din pacienti cu ACM GH creste cu minimum 50%.

GH bazal (random)<0,4ng/ml exclude ACM


Teste de functie hipofizara : PRL, 9 a.m. plasma cortisol
(ITT), E2/testosteron , FSH, LH, TSH, fT4

Calciu, triglycerides, cholesterol

Imagistica: CT/ MRI hipofizar


Imunohistochimia tumorii

Radiografia de sa turceasca
1-clinoide anterioare;
2-planseu selar;
3-sinus sfenoid
4-lama patrulatera;
5.clinoide
posterioare;
6. stanca temporala;
7. clivus.

15/12/19 mm (lungimea, adncimea adncimea i respectiv limea


seii turcesti)

TRATAMENT
1.Chirurgia trans-sfenoidala a tumorii :
vindecare: 40-90% microadenoame;10-50% in macroadenoame
recurenta 6% la 5 ani
2. Radioterapie

Conventionala fractionata de inalt voltaj

Radiochirurgie Gamma-knife

Impanturi cu materiale radioactive abandonata

3. Tratament medicamentos:

Analogi Somatostatin : octreotide/lanreotide

Antagonist al receptorului pt GH : Pegvisomant

Agonisti dopamina : Bromocriptina/Cabergolina

Medical therapy in
acromegaly
Somatostatin analogs

Octreotide s.c. (Sandostatin)


1 inj at 8 hours
Lanreotide i.m (Somatuline)
1 inj at 10-14 days
Octreotide LAR i.m. (Sandostatin LAR)
1 inj at 28 days
Lanreotide Autogel s.c. (Somatuline Autogel) 1 inj at 28 days

GH Receptor Antagonist
Pegvisomant

OCTREOTIDE AS PRIMARY MEDICAL


THERAPY FOR ACROMEGALY
GH serum levels:
N=27, octreotide 300-600 g 24 wk
N=15 Oct-LAR 24 wk

Tumors shrank 43-49%


Serum GH<2.5 g/L 79%
Serum IGF1 normal 53%

Bevan J et al, JCEM, 2002, 87: 4554

GH binding on GHR
GH

GH
Site 1
Binding

Pre-formed
GHR Dimer
Cell Surface

GH

GH

Site 2
Binding

Functional GHR Dimerization

Signal
Transduction

Generation of
IGF-l

GH: growth hormone; GHR: GH receptor.


Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.

GHRA (pegvisomant,SOMAVERT)- structure


PEG
Moiety
PEG
Moiety

GHRA

Site
2: 2:
Site
1 Amino
Acid
Substitution
1 Amino
Acid
Substitution

Site 1:
8 Amino Acid
Substitutions

Pre-formed
GHR Dimer

Cell Surface

GHRA: GHR antagonist; PEG: polyethylene glycol.


Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.

GHRA - mechanism of action

GHRA

Site 2
Binding

Site 1
Binding

Highly selective for GHR


Long half-life (6 days)

Site 2
Binding
Peak serum levels: 33-77
h

Reduced immunogenicity
Internalization not impaired
No
Signal
Transduction

No
Generation
of IGF-l

Improper or Nonfunctional
GHR Dimerization
Adapted from Kopchick JJ. Presented at: Global Endocrine Summit: Focus on Acromegaly; November 7-8, 2003; Barcelona, Spain.

Radioterapia adenoamelor hipofizare


Conventionala fractionata, de inalt
voltaj (45 50 Gy, 1.8 2Gy/sedinta)

Gamma- knife (doza inalta, administrare


unica)

Eficacitatea tratamentului in acromegalie


Treatment
Transsphenoidal surgery

Safe GH (%)

Normal IGF-I (%)

Tumor size
reduction

2365 (Macro)

Yes

Outcome dependent on
expertise of surgeon,
pretreatment GH, tumor
position

90

6080

Yes

Efficacious but slow (up to 18


yr) reduction of GH and IGF-I

1020

1043

May be seen
in PRL
cosecreting
tumors

2255 (sc)

45 (sc)

Uncertain

6070 (LA)

5060 (LA)

6090 (Micro)
Conventional radiotherapy
Dopamine agonists

SMS analog

Comments

More efficacious in PRL


cosecreting tumors

Tumor shrinkage in selected


patients, no randomized studies

LA, Long acting; macro, macroadenoma; micro, microadenoma


Kopchick JJ et al, Endocr Rev, 2002, 23 (5): 623-646

Aggressive acromegaly
TZ, male, 32 yr
+ Left eye hemianopia
+ Central
hypogonadism
normal PRL

CT: Macroadenoma 3.5/3.6 cm


OGTT 75 g

30

60

120

Glycaemia (mg/dl)

108

179

191

161

GH (ng/ml)

78

77

87

84

IGF1 (116307 ng/ml)

677

Aggressive acromegaly
post 2nd surgery (craniotomy)
3.4 /
2.2
cm

Before

After

3.0 /
1.4
cm

Diabetes insipidus, hypopituitarism, neuroophtalmic aggravation,


improved diabetes mellitus

Aggressive acromegaly
surgery (SS + FS), SSA (lanreotide), gamma knife, SSA
(octreotide 30 mg/month), pegvisomant
100
80
60
40

77
677

885

855
774

793

62.2

60
36.9

35.3

29.3

20
0

Time
Nadir GH (ng/ml)

IGF1 (ng/ml)

1000
900
800
700
600
500
400
300
200
100
0

IGF1

Nadir GH in OGTT

After

PROLACTINOMUL
(TUMORA LACTOTROFA)

Cautati galactoreea!

CAUZE DE HIPERPROLACTINEMIE
1.
2.
3.
4.
5.
6.

Fiziologice: sarcina, actul sexual, stimularea mamelonului/suptul, stresul


Tumora hipofizara: prolactinom/ macroadenom care comprima tija
Boala hipotalamica: craniofaringiom, meningiom, sarcoidoza
Sectionarea tijei: traumatism cranian, chirurgie
Iradiere craniana
Medicamente:
Antagonist de receptor de dopamina (metoclopramide, domperidome)
Estrogeni
Neuroleptice (exceptie: clozapine, quetiapine, olanzapine)
Antidepresive (MAOI, SSRI, tricyclics)
Opioide
Cardiovasculare (verapamil, methyldopa)
Inhibitori proteaza (zidovudine, ritonavir, indinavir)
Altele ( benzafibrate, omeprazole, H2 blockers)
7. Hipotiroidism
8. PCOS
9. Boala renala/hepatica cronica
10. Leziuni de perete toracic (inclusiv zona zoster)
11. Macroprolactinemia

TRATAMENT
Obiective: MicroPRL: restabilirea functiei gonadale
MacroPRL: - reducerea dimensiunii tumorii
- prevenirea expansiunii tumorii
- restabilirea functiei gonadale
Medicamentos: Agonisti dopamina
Bromocriptina 7,5 mg 15 mg/day
Cabergolina 0,5 3 mg /week
Chirurgical:
rezistenta/intoleranta la agonisti dopaminergici
MacroPRL cu fistula LCR (prolactinom invaziv )

Radioterapie: cand medicamentele +/- chirurgia esueaza, de o


in tratamentul macroprolactinoamelor

BOALA CUSHING
(ADENOM HIPOFIZAR CORTICOTROF)

Tablou clinic
Facies: rotund, pletoric, acnee, hirsutism, rarirea pilozitatii scalpului
Crestere ponderala: obezitate tronculara cartof pe scobitori), ceafa
de bizon , depozite adipoase supraclaviculare
Piele: subtire si fragila, vergeturi purpurice pe abdomen, sani, coapse,
axile, vanatai instalate rapid, uneori hiperpigmentatie datorita excesului
de ACTH
Scaderea fortei musculaturii proximale (- genuflexiuni)
Tulburari de dispozitie, labilitate, depresie, insomnie, psihoza
Dereglari menstruale / Libidou scazut, disfunctie erectila
Oprirea cresterii la copil

COMPLICATII
1. HIPERTENSIUNE (>50%)
2. DIABET ZAHARAT(30%)/ TOLERANTA
ALTERATA LA GLUCOZA (40%)
3. OSTEOPENIE/OSTEOPOROZA
4. BOALA VASCULARA
5. COAGULOPATII
6. SINDROM METABOLIC
5. SUSCEPTIBILITATE LA INFECTII

INVESTIGATII
1. Cortisol liber urinar /24h crescut
2. Pierderea ritmului circadian
Ora 23- 24 cortizol >50nmol/l (sau de 5ug/dl)
3. Teste de supresie la Dexametazona
Overnight 1mg;
DXM 2mg x 2 zile
DXM 8mg x 2 zile
4. ACTH
5. Cateterism de sinus pietros inferior
masoara ACTH si cortisol dupa CRH (100mcg i.v.)
raport central:periferic >2 inainte de CRH
raport central:periferic >3 dupa CRH
6. K seric <3.2 mmol/l caract in sd Cushing ectopic
7. Imagistica hipofizara: MRI (80% microadenoame)

Cauzele sindromului Cushing


ACTH-dependente (80%):
adenom hipofizar 68% (Boala Cushing)
ACTH ectopic 12%
CRH ectopic <1%
ACTH-independente (20%):
adenom adrenal
carcinom adrenal
hiperplazia adrenala nodulara
Sindrom pseudo-Cushing :
alcooolism
depresie severa

Tratamentul bolii Cushing


1. Chirurgie hipof. trans-sfenoidala
Criteriu de vindecare: cortisol nedetectabil la ora 8 9
a.m. (<50nmol/l sau 5 ug/dl)
2. Radioterapie hipofizara
3. Suprarenalectomie bilaterala
4. Tratament medicamentos:
Preop.: metyrapone/ ketoconazole/aminogluthetimide
Postop. daca cortisol scazut: substitutie cu glucocorticoizi
Daca SR-ectomie bilaterala: adaugam si substitutie
mineralocorticoida

Sindromul Nelson

hiperpigmentare +
tumora hipofizara in
dimensionala +
ACTH foarte crescut

evolutie

apare la pana la 30% in 2 ani dupa


adrenalectomie

TIROTROPINOAME
Rare, 1% din adenoamele hipof; 90% macroadenoame
produc TSH / TSH+GH /TSH+PRL
Dg: - hipertiroidism cu TSH crescut sau normal
- alpha subunits :TSH >1
- test la TRH : raspunsul TSH absent dupa TRH;
(diferentiaza tumorile TSH- secretante de rezistenta la hh. tiroidieni)
- MRI:

macroadenom hipofizar

Tratament: Chirurgie vindeca 1/3, amel 1/3;


Radioterapie dupa chirurgie incompleta
Analogi de somatostatin (octreotide)
N.B. Evitati medicatia anti-tiroidiana !

ADENOAME HIPOF. CLINIC NEFUNCTIONALE


Cea mai frecventa tumora hipof : 25%
Tablou clinic
-Efecte de masa: cefalee, tulburari de camp vizual, oftalmoplegie,
atrofie optica, apoplexie hipofizara
- hipopituitarism: 50% au deficit gonadotrop la prezentare
- uneori descoperite incidental (incidentalom)
Investigatii
- MRI hipofizar
- evaluare camp vizual
- PRL (dg diferential cu prolactinomul!)
- evaluarea functiei hipofizare.
- imunohistochimie:
negative (null cell tumors/ oncocytoma)
ACTH (silent corticotroph)
gonadotropi/ alpha subunits

Managementul NFPA

1. Chirurgie
2. Radioterapie
3. Medical: substitutia hipotiroidismului

CRANIOFARINGIOAMELE
Tumori cu originea in resturile epiteliale ale pungii Rathke.
Benigne, local infiltrative
Localizare: suprasellara/ intrasellara sau ambele
Este cea mai frecventa tumora cerebrala la copil
Histologie: - epiteliu adamantinos cu formare de chisturi si calcificari
- hCG prezent in fluidul chistic.
Tablou Clinic :
- Presiune intracraniana crescuta la copii
- tulburari de vedere
- diabet insipid
- hipopituitarism
- obesitate
MRI: masa tumorala cu chisturi si calcificari
Tratament: chirurgie, urmata de radioterapie , mai ales daca resturile tum sunt
vizibile sau evolutive postop