Tumorile hipofizare

Corin Badiu

Corin Badiu, 2018

 Tumori hipofizare
• Definitie
• Clasificare histopatologica si neuroradiologica
• Tablou clinic
• Investigaţii
– Hormonologie
– Imagistică
• Diagnostic pozitiv si diferential
• Etiologie si patogenie
• Anatomie patologica
• Fiziopatologie
• Evolutie, complicatii
• Tratamentul tumorilor hipofizare
– Obiective: etiologic, fiziopatologic, substitutiv
– Mijloace terapeutice
– Urmărirea eficienţei terapiei
• Concluzii
Corin Badiu, 2018
 Tumori hipofizare

Definitie: Adenoame hipofizare benigne, clinic secretante

/nesecretante, intraselare /cu extensie supraselara, rareori ADK
hipofizare, insotite de complicatii endocrine (hipopituitarism,
diabet zaharat), neurologice sau oftalmologice.

Corin Badiu, 2018

 Clasificare
Histologic (MO): cromofobe - 70%, PRL 50%
acidofile – 15%, GH si PRL
bazofile – 15%, ACTH

Adenoame secretante:
20% GH  acromegalie
35% PRL  prolactinom
7% GH + PRL
7% ACTH + MSH  boala Cushing si sd Nelson
20% LH, FSH, TSH
Adenoame nesecretante:
10% cu celule foliculostelate, oncocitom

Corin Badiu, 2018

Clasificare

Corin Badiu, 2018

 Clasificare neuroradiologica
Hardy:
Stadiul I – microadenom, < 10 mm
II – macroadenom, cu expasiune
III – invaziv localizat
IV – invaziv difuz

Knosp: Stadii I-IV

Corin Badiu, 2018

 Tablou clinic
Sindrom endocrin: Sindrom neurologic:
Acromegalie/ gigantism; Sd Neurooftalmic
sd Amenoree - Galactoree; Leziuni n cranieni III, IV, VI
Cushing; Melanodermie; HIC (cefalee, varsaturi, edem papilar)
Hipopituitarism Rinoliquoree
Epilepsie temporala

Sindrom metabolic:
DZ secundar
obezitate / casexie HPT

Corin Badiu, 2018

 Tablou clinic
Sindrom endocrin:
Acromegalie/ gigantism;
sd amenoree-galactoree;
Cushing; Melanodermie;
Hipopituitarism

Corin Badiu, 2018

Gigant si pitic

Cel mai scund om din lume-

chinezul He Pingping, (73 cm)
si cel mai inalt -
turcul Sultan Kosen (246 cm).

Corin Badiu, 2018

 Acromegaly: Outside

Without Acromegaly With Acromegaly

• Normal blood pressure • Increased risk of cardiovascular disease
• Respiratory conditions and intrinsic
• Normal breathing patterns lung disease
• Normal sleep pattern • Sleep apnea

Corin Badiu, 2018

Acromegaly: Outside

Corin Badiu, 2018

Cushing
Tabloul clinic in Cushing
 Cushing Syndrome

Autonomous excess of endogenous cortisol secretion ± androgens and

mineralocorticoids

• ACTH dependent 82%

Pituitary ACTH 66%
Ectopic ACTH 12%
Unknown source ACTH 4%

• ACTH independent 18%

Adrenal adenoma 10%
Adrenal carcinoma 7%
• Macronodular Hiperplasia 1%
ACTH dependent Cushing

André Lacroix, Richard A Feelders, Constantine A Stratakis, Lynnette K

Nieman Cushing Syndrome Lancet 2015; 386: 913–27
Adrenal Axis
• CRH / VP
• ACTH
• Cortisol
• Leptina
• Citokines
• GR, CRHR, V1b, ACTH R,
 Circadian Rhythm

Stres
600
Plasma
[ cortisol ]
(nmol/L)

100

00:00 06:00 12:00 18:00 00:00

Timp
Cushing
Cushing
 Non Neoplastic hypercortisolism /
Subclinical Cushing disease ?
What pathologic conditions?

Psychatric +++ : Depression, other (severe)

Chronic stress, Obesity, alcoholism,
Renal insufficiency

Physiopathology?
Functional CRH Hypersecretion

Differential diagnosis
Moderate Cushing’s disease / subclinical Cushing
 NN Hypercortisolism Cushing’s disease

Stress, Obesity
Alcoholism
_ Loss of
Preservation of CRF • Cycle
• Cycle HYPOTHALAMUS • Feed back
• Feed-back CRF
PITUITARY Sensitive to
Poorly sensitive • Exog.CRH
to ACTH
• ddAVP
• Exog. CRH ACTH
• ddAVP

ADRENAL

cortisol
cortisol
Dynamic testing
Diagnostic in Cushing Syndrome
Inferior Petrosal Sinus Sampling

Femural V. IPS
CRH 100 ug i.v.
Control - VCI
IPS: -5, 0, 2, 5, 10 min
 Insuficienţa adenohipofizara
• Deficit de RH
• Afectarea sintezei adenohipofizare
• Transportul şi metabolismul hormonilor
• Resistenţă la acţiunea hormonilor

1. Invaziv (Ad hip, CRF, meta) 5. Infecţioasă (TBC, micoze)

2. Infiltrativ (Hist, Sarc, Hemocr.) 6. Impact traumatic (sect. tija)

3. Infarct (apoplexie AH, Sheehan) 7. Imunologic (hipofizita)
4. Iatrogen (Op, Rxt) 8. Izolată (Kallman sau pluritropa)
9. Idiopatică

Corin Badiu, 2018

 Funcţia adenohipofizară
Corticotroph Gonadotroph Thyrotroph Lactotroph Somatotroph

Hormone POMC, ACTH FSH, LH TSH Prolactin GH

Stimulators CRH, AVP, gp-130 GnRH, Estrogen TRH Estrogen, TRH GHRH, GHS
cytokines

Inhibitors Glucocorticoids Sex steroids, T3, T4, Dopamine, Dopamine Somatostatin,

inhibin Somatostatin, IGF-1,
GH Activins

Target Gland Adrenals Ovary, Testes Thyroid Breast and other Liver, bone and
tissues other tissues

Trophic Steroid production Sex Steroid, T4 synthesis and Milk Production IGF-1 production,
Effects Follicular secretion Growth
growth, Germ induction,
Cell Insulin
maturation antagonism

Adapted from: William’s Textbook of Endocrinology, 10th2018

Corin Badiu, ed.
Corin Badiu, 2018
Corin Badiu, 2018
 Tipuri celulare in pars distalis
Cell Type Secretory Products Cell Population %

Somatotroph Growth hormone 50

Lactotroph Prolactin 15

Corticotroph Adrenocorticotropic hormone 15

Thyrotroph Thyroid stimulating hormone 10

Gonadotroph Luteinizing hormone- 10

Follicle-stimulating hormone

N.B.: aceste procente se modifică în diferite stări fiziologice (sarcina:

GH→PRL) sau patologice (mixedem: GH→TSH; hipogonadism primar,
climax GH → FSH, LH), prin transdiferentiere

Corin Badiu, 2018

 Înrudiri celulare în adenohipofiza

Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002

O celula – un hormon?
Burrows et al, TEM Corin
10, 344, 1999
Badiu, 2018
 TRANSDIFERENTIERE

GH cells (FITC, green) to TSH cells (Txred) transdifferentiation in

hypotyhroid rat at 21 d (B) and 28 d (C)
Radian S et al, J.Cell.Mol.Med., Corin
7, 297, 20032018
Badiu,
Corin Badiu, 2018
Corin Badiu, 2018
Corin Badiu, 2018
Sindrom tumoral

Corin Badiu, 2018

Paraclinic - Imagistic
Radiografia de sa turca

Corin Badiu, 2018

Paraclinic - Imagistic
Radiografia de sa turca

Corin Badiu, 2018

Paraclinic - Imagistic
Tomografia computerizata

Corin Badiu, 2018

Prolactinom invaziv Craniofaringiom

Corin Badiu, 2018

 IRM normal

Corin Badiu, 2018

Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987
IRM normal

Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone

Corin Badiu, 2018

Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987
Paraclinic - Imagistic
IRM

Corin Badiu, 2018

 Tumori hipofizare (Prolactinom)
• Amenoree-galactoree
• Efect de masă (SChO, obstructie nazală)
• Hipopituitarism
• PRL: 5700 ng/ml

Corin Badiu, 2018

Craniofaringiom

Corin Badiu, 2018

Metastaze hipofizare

Corin Badiu, 2018

Hipoplazia hipofizară

Corin Badiu, 2018

 Sheehan

FSH=nd, T3=102 ng/dL, T4= 3 mg%, cortisol=12 mg%

Corin Badiu, 2018

 Paraclinic - Imunoassay
Teste bazale si dinamice: exces- supresie;
deficit clinic- inhibitie
GH → OGTT 0, 30, 60, 90, 120 min (ACM) : 1 ng/ml
PRL → 20 ng/ml → → → 100 ng/ml → → → 10000 ng/ml
ACTH, cortizol in DXM ON, 2x2, 2x8
LH si FSH la femeile la menopauza
T4, T3, fT4, fT3 , TSH

Corin Badiu, 2018

Reacţia antigen-anticorp

Ag + Ac*  Ag Ac*

Corin Badiu, 2018

Specificitatea anticorpilor şi reactivitatea
încrucişată

Corin Badiu, 2018

 Oral Glucose Tolerance Test

Acromegaly:
positive & differential
diagnosis
Diabetes Mellitus

Oral glucose 75g

GH peak level > 1 mg/L
Corin Badiu, 2018
IGF-1: variaţii cu vârsta şi sexul

Corin Badiu, 2018

 Circadian Rhythm in Plasma ACTH and Cortisol in a Clinically Healthy 
Adult Women Sampled at 20 minute Intervals

Plasma ACTH Plasma Cortisol
* * 828
6.6 * * * * * *
* * 690
5.5 *

Cortisol (mU/L)
*
ACTH (mU/L)

* * 552
4.4 *
* *** * 414
3.3 *
* * *
2.2 276 *
* *
1.1 138 * *
*

12:00 16:00 20:00 00:00 04:00 08:00 12:00 12:00 16:00 20:00 00:00 04:00 08:00 12:00
Time (Clock Hour)

Corin Badiu, 2018

 Precauţii în evaluarea hipopituitarismului

• Obezitate (GH, cortizol în ITT)

• Diabet zaharat (valori GH>, IGF1<)
• Insuf. Renala cronica (GH, PRL, TSH, FSH, LH, CLU>)
• Anorexia nervoasa şi caşexie (GH>; E2/T<, cort>)
• Hipercorticism endo sau exogen (TSH, FSH, LH<)
• Depresie (cortizol>, TSH<)

Corin Badiu, 2018

Insulin Tolerance Test
0.1/0.15 UI/Kgc, i.v.
Obezi: 0,3 UI/Kgc

Contraindicate
Comitialitate
Boală cardiacă ischemică

Corin Badiu, 2018

Reglarea Axei Gonadice
• GnRH
• LH & FSH
• Prolactina
• Testosteron /E2, Pg
• Inhibina /activina

Corin Badiu, 2018

Pulsatile LH Pattern in Human

Corin Badiu, 2018

Reglarea Axei Tiroidiene
• TRH
• TSH
• T4 / T3
• Type II deiodinase
• Leptina
• TR, TRH R, TSH R

Corin Badiu, 2018

Test la TRH

400 mg i.v. TRH

TSH se măsoară la
fiecare 30 min, 3 h

Corin Badiu, 2018

Reglarea Axei CSR
• CRH / VP
• ACTH
• Cortisol
• Leptina
• Citokine
• GR, CRHR, V1b, ACTH R,

Corin Badiu, 2018

 Testul scurt de Stimulare cu ACTH
Cortisol (mg%)

250 mg ACTH i.v.

Corin Badiu, 2018

 Diagnostic diferential
• Sa turca larga
– constitutional, LCR, vase (anevrism de carotida, sunturi
intercavernoase), chist dermoid, arahnoidian, tumori- gliom optic
• Galactoreea – hiperprolactinemii functionale
• Acromegalie – acromegaloidie
• Melanodermie
• Sd Cushing si sd Cushingoide
• Insuficiente primare: gonade, mixedem, Addison

Corin Badiu, 2018

 Diagnostic diferential

Sa turca larga Acromegalie

Corin Badiu, 2018

Model al tumorigenezei hipofizare

Heaney & Melmed, Endocrine related cancer, 7, 2000

Corin Badiu, 2018
Corin Badiu, 2018
 Anatomie patologica
NFA, TSH & FSH IR

BI, M, 37 y, IV SSE NFA, Sindrom Optochiasmatic

TSH(c/s) = 3.54/2,18; LH (c/s) = 6.96/1.53 mU/ml, FSH (c/s) = 39.66/18

TSH - ICC FSH ICC

Corin Badiu, 2018
 Fiziopatologie
Hormon excesiv/ deficitar
Sindrom tumoral – compresii N II, III, IV, VI
Evolutie: reevaluare in timp 6 luni, 1 an, 3 ani, 5 ani
Complicatii: neurooftalmice, metabolice, HTA,
hipopituitarism, apoplexie hipofizara

Corin Badiu, 2018

 Sindromul Nelson
Boala Cushing post SRectomie
bilaterala 
defrenaj hipofizar, melanodermie,
macroadenom invaziv.

Corin Badiu, 2018

Tratament

Corin Badiu, 2018

Tratament etiologic

Corin Badiu, 2018

Pituitary tumorigenesis
 Treatment
Historical perspective
Cushing’s disease treatment goals

Normalization of
biochemical
changes with
minimal morbidity
Long-term
Reversal of
control
clinical
without
features
recurrence

Treatment
goals

Nieman et al, . J Clin Endocrinol Metab, 2015, Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462
Fleseriu M & Petersenn S. J Neurooncol 2013;114:1–11.
 Algorithm for Management

Pituitary surgery
Patients with persistent disease after pituitary surgery

Repeat Medical Bilateral

adrenalectomy Radiation
surgery therapy
• Which patients should be considered for medical therapy?
¨ Severe co-morbidities/high surgical risk
¨ While awaiting effect of radiotherapy
¨ Adenomas with an unfavorable location for further surgery
¨ Non-visible adenomas in the absence of a dedicated pituitary
surgeon
Nieman et al, . J Clin Endocrinol Metab, 2015, Fleseriu, Pituitary 2012, Fleseriu M, Endo Clin N
Am. 2015, Biller BMK et al. J Clin Endocrinol Metab 2008
 Medical Therapy

ns
tio
na
bi
om
+C
Fleseriu. Endo Clinics of North
Fleseriu. Neurosurg Clinics. 2012, Oct;23(4):653-68 America, 2015
 Pasireotide
• Multiligand SRL, 600 or 900 mcg twice
a day subq.
• FDA and EMA- approved for CD, Dec
2012

12 mos: UFC normalization:

13% ( 600 µg)
25% (900 µg)
•Significant clinical improvement,
even in patients without UFC
normalization

• Safety similar to other somatostatin

analogues with the exception of
degree & severity of hyperglycemia

Fleseriu, Petersenn. Pituitary. 2012 Sep;15(3):330-41, Fleseriu, J

Neurooncol. 2013 Aug;114(1):1-11.
 Predictive factors for response?

• Mild Cushing’s

• Early normalization of UFC and/or LNSC: 90% of nonresponders at

2 months did not normalize later
• Acute Pasireotide suppression test (sc 600 μgX1): LNSC fall >27 %
had PPV 100 %, NPV 75 %
Escape?
•Colao et al.N Engl J Med. 2012 , Trementino L et al, Endocrine. 2015, Fleseriu M et al, AACE disease state review, 2016
 Tumor shrinkage with Pasireotide

Substudy 8 patients: Pasireotide induced tumor shrinkage regardless of UFC status

¨ 62.5 % of patients at 6 months
¨ 100 % of patients after 12 months

Baseline 6mo

12 mo 24 mo

Simeoli et al, Endocrine, 2015, Shimon I et al. Pituitary 2012

Novel medical therapies

Efficacious

Safe and Cost

well tolerated effective

Ideal
medical
agent
Favourable Patient
PK profile satisfaction

High
adherence to
treatment
Corin Badiu, 2018
Corin Badiu, 2018
 Tratament substitutiv
• Principii:
– Ordinea (axa vitala!)
– Administram Hh. gl. Ţinta
– Rata secreţiei, ritm
• CSR – Cortizon acetat (20-30 mg) sau Pdn, alternând
cu ACTHa (+ sinteza Androgeni, Cortizol şi trofic)
• Tiroidian (T4, ± T3, 100 mg/zi); rhTSH (în KK tir)
• Gonadic: (E2/Pg);
• Fertilitate: (FSHa, LHa) diferit la ♂ faţă de ♀
• GH (opţional, costuri↑)

Corin Badiu, 2018

 CONCLUZII
• Evaluare imagistica de inalta rezolutie

• Evaluarea bazala, dinamica in inhibiţie sau stimulare

• Integrarea rezultatelor clinice, biochimice, imagistice.

• Tratament specific, selectiv

Corin Badiu, 2018