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
La normali 200mcg TRH i.v. determina supresia GH. La 80% din pacienti cu ACM GH creste cu minimum 50%. or IGF

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 Analogi Somatostatin : octreotide/lanreotide Antagonist al receptorului pt GH : Pegvisomant Agonisti dopamina : Bromocriptina/Cabergolina

3. Tratament medicamentos:

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 Site 1 Binding Pre-formed GHR Dimer

GH

Cell Surface

GH

Site 2 Binding

GH

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 1 Binding

Site 2 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 (%) 2365 (Macro) 6090 (Micro) Conventional radiotherapy Dopamine agonists 90 1020 6080 1043 Yes May be seen in PRL cosecreting tumors Uncertain Normal IGF-I (%) Tumor size reduction Yes Comments Outcome dependent on expertise of surgeon, pretreatment GH, tumor position Efficacious but slow (up to 18 yr) reduction of GH and IGF-I More efficacious in PRL cosecreting tumors

SMS analog

2255 (sc) 6070 (LA)

45 (sc) 5060 (LA)

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 Glycaemia (mg/dl) 0 108 30 179 60 191 120 161

GH (ng/ml)
IGF1 (116307 ng/ml)

78
677

77

87

84

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

100

77
677

885 774 60 36.9 29.3 62.2

1000 800 600 400 200 0

Nadir GH

80 60 40 20 0

Baseline

Postsurgery Post SSA 6 mth

Post 2nd Post 2nd surgery (1 mth) surgery (2 mth)

Time
Nadir GH (ng/ml) IGF1 (ng/ml)

IGF1

Aggressive acromegaly surgery (SS + FS), SSA (lanreotide), gamma knife, SSA (octreotide 30 mg/month), pegvisomant
After
100 80 60 40 20 0
6m 5m e ry 1 m) 2 m) line ery ( ery ( m + OCT tsurg ost LAN Ba se Pos surg surg P 8 2nd 2nd st st st GK Po Po Po 2m Pegv

Nadir GH in OGTT

77
677

885 774 60 36.9 29.3 62.2

855 793

35.3

1000 900 800 700 600 500 400 300 200 100 0

Time
Nadir GH (ng/ml) IGF1 (ng/ml)

IGF1

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