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-hipofizarDescoperirea 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 HIPOFIZAREBenigne (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: microadenom1cm 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 GHSimptome 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)

COMPLICATII1. 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 glucozaLipsa de supresie a GH < 1ng/ml = acromegalie

IGF1 crescut pentru varsta si sex TRH test numai la pacientii cu rezultate echivoce in OGTTLa normali 200mcg TRH i.v. determina supresia GH. La 80% din pacienti cu ACM GH creste cu minimum 50%. or IGF

GH bazal (random)

Radiografia de sa turceasca1-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)

TRATAMENT1.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 ACROMEGALYGH serum levels: N=27, octreotide 300-600 g 24 wk N=15 Oct-LAR 24 wk

Tumors shrank 43-49% Serum GH

GH binding on GHR

GH Site 1 Binding Pre-formed GHR Dimer Cell Surface

GH

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)- structurePE GG Moiety PE 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 impairedNo Signal Transduction No Generation of IGF-l

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

Radioterapia adenoamelor hipofizareConventionala fractionata, de inalt voltaj (45 50 Gy, 1.8 2Gy/sedinta)

Gamma- knife (doza inalta, administrare unica)

Eficacitatea tratamentului in acromegalieTreatment 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) GH (ng/ml) IGF1 (116 307 ng/ml) 0 108 78 677 30 1 79 77 60 191 87 120 161 84

Aggressive acromegaly post 2nd surgery (craniotomy)3.4 / .2 c Before After 3.0 / 1.4 c

D betes insipidus, hypopituit ris , neuroopht l ic aggravation, improved diabetes mellitus00 0 rG 0 40 0 0aseline Pos ts urg ery Pos t A mt Pos t 2 nd Pos t 2 nd s urg ery ( mt ) s urg ery (2 mt ) (ng ml )0

7777 0

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774

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eadir GH (ng ml ) G

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Aggressive acromegaly surgery (SS + FS), SSA (lanreotide), gamma knife, SSA (octreotide 30 mg/month), pegvisomantAfter1000 900 800 700 600 500 400 300 200 100 0

ir GH in OGTT

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t A t

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( m) er ( m) O T 5m r e r r m+ K t tG

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Timeadir (ng/ml ) F1 (ng/ml )

IGF1

PROLACTINOMUL (TUMORA LACTOTROFA)

Cautati galactoreea!

CAUZE DE HIPERPROLACTINEMIEFiziologice: 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 1. 2. 3. 4. 5. 6.

TRATAMENTObiective: 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 ob 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

COMPLICATII1. 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

INVESTIGATII1. 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

Cauzele sindromului CushingACTH-dependente (80%): adenom hipofizar 68% (Boala Cushing) ACTH ectopic 12% CRH ectopic

Tratamentul bolii Cushing1. Chirurgie hipof. trans-sfenoidala Criteriu de vindecare: cortisol nedetectabil la ora 8 9 a.m. (

Sindromul Nelson hiperpigmentare + tumora hipofizara in dimensionala + ACTH foarte crescut

evolutie

apare la pana la 30% in 2 ani dupa adrenalectomie

TIROTROPINOAMERare, 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 NEFUNCTIONALECea 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

CRANIOFARINGIOAMELETumori 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