NEOPLAZIILE ENDOCRINE MULTIPLE Prof. Dr. Carmen Georgescu Clinica Endocrinologie, Universitatea de Medicina si Farmacie “Iuliu Hatieganu” Cluj-Napoca, Romania
NEOPLAZIILE ENDOCRINE MULTIPLE
Prof. Dr. Carmen Georgescu
Clinica Endocrinologie, Universitatea de Medicina si Farmacie “Iuliu Hatieganu” Cluj-Napoca,
Romania
SUBTIPURILE MEN
• Neoplaziile Endocrine Multiple (Multiple Endocrine Neoplasia)
= sindroame endocrine maligne = transmitere AD = presupun afectarea a cel putin 2 glande endocrine [MEN1]
• MEN1
• MEN2 • MEN2A • MEN2B • Carcinomul Medular Tiroidian (CMT) familial
• MEN 4 (varianta MENX la specii murine)
Diagnostiul MEN1
DIAGNOSTICUL POZITIV
MEN1
CLINIC
Pacient cu 2 sau mai
multe tumori MEN1-
like
ISTORICUL
FAMILIAL
Pacient cu tumori
MEN1-like avand 1
ruda de gradul I cu
MEN1 confirmat
GENETIC
Individ cu mutatie
MEN1 fara elemente
de diagnostic clinic
sau biochimic
prevalenţa 1/30.000 sau 2-20/100.000 din populaţia generala penetranţa maximă în decada a 5-a
CLINICA IN NEOPLAZIA ENDOCRINA MULTIPLA (MEN) 1
PATOLOGIE ENDOCRINA Penetranta estimata (%)
ADENOM/HIPERPLAZIA GLANDELOR PARATIROIDE 95
GASTRINOM DD-PANCREATIC 40
INSULINOM 10
Glucagonom, VIPom etc. oricare <1
PanNet NEFUNCTIONALE (inclusiv polipeptidomul pancreatic) 20
Tumora carcinoida – intestin anterior/ timic 2
Tumora carcinoida bronsica 4
Tumori enterocromafine gastrice nefunctionale 10
ADENOM HIPOFIZAR 10
PRLom 25
Adenom nefunctional 10
GHom+PRLom 10
GHom 5
ACTHom 2
TSHom 5
Tumora suprarenala 30
functionala sau maligna 2
Feocromocitom < 1
colagenoame faciale (MEN 1)
PATOLOGIE NEENDOCRINA
Penetranta estimata (%)
ANGIOFIBROM 85
COLAGENOM 75
LIPOM 30
LEIOMIOM (inclusiv uterin)
25
MENINGIOM 5
EPENDIMOM rar
CLINICA IN NEOPLAZIA ENDOCRINA MULTIPLA (MEN) 1
Calciu ionic 5.45 mg/dl 4.2-5.4
Calciu total 12.3 mg/dl 8.4-10.5
TSH 1.12 uU/ml 0.5-4
FT4 0.96 ng/dl 0.8-2
ATPO 10 U/l <50
ATG 20 WhoU <60
Calcitonina <2 pg/ml <13
iPTH 456.1 pg/ml 15-68.3
HIPERPARATIROIDISM PRIMAR
CT ABDOMINO-PELVINA
cranial & anterior de capul pancreasului - formatiune de 23/15
mm, 34/27 mm (in evolutie)
caudal de procesul uncinat – tumora de 18 mm
GASTRINOM
Diaree
Epigastralgii
Pirozis
Sindrom Zollinger-Ellison
Cromogranina A 766.002 ug/L 27-94
Glucagon 74 ng/L 60-177
VIP 3.1 pmol/l <17
Serotonina 226 ug/L 80-400
5-HIAA 9.7 mg/24 h 2-9
Gastrina internarea initiala 2718 pg/ml 13-115
la 1 an 5480 pg/ml 13-115
GASTRINOM Gastrina
• Insulinomul
• 4-6% din cazuri apartin MEN1
• triada Whipple +
• glucozaplasm<55mg/dl, insulinaplasm≥3μU/ml,
peptid C≥0.6ng/ml, Ac Anti-insulina absenti
SAU testul de foame (72h)
• PanNET nefunctionale
• durere abdominala, greata, varsaturi, scadere
ponderala
• Glucagonomul • 1-2% din cazurile MEN1*
• Eritem necrolitic migrator, DZ, casexie
• Glucagon
• Somatostatinomul • 1% din cazurile MEN1*
• DZ, LB, steatoree
• Somatostatina
• VIPomul • <1% din cazurile MEN1*
• diaree apoasa, hipoK, aclorhidrie, DZ
• VIP , PP
*Groupe des Tumeurs Endocrines (GTE)
PanNET Rare asociate
MEN1
Cromogranina A
- markeri NE nespecifici (CgA)
- expresia
- in tumori slab diferentiate
- in tumori nefunctionale
- /Nin tumori mici
- valoare postterapeutica inalta
!CgA fals pozitiva - IRC
- Inhibitorii pompei de protoni
- Gastrita cronica
- HTA
Cromogranina A
Expresia CgA variaza in raport cu originea tumorii primare
Vinik AI, et al. Pancreas. 2011;39:713–34.
CT ABDOMINO-PELVINA
formatiune nodulara intens iodofila 18 mm 24 mm (in evolutie)
Cortizol ora 8 166 ng/ml 70-225
Cortizol post Bricaire 9.62 ng/ml <50
Renina plasmatica 15.1 pg/mL 1.68-23.94
Aldosteron seric 48 pg/mL 29.4 - 161.5
Raport aldosteron/renina 3.17 <54
Metanefrine plasmatice 20.6 pg/ml <90
Normetanefrine plasmatice 15.4 pg/ml <180
• TUMORILE GLANDELOR SUPRARENALE ASOCIATE MEN1
• ~ 20-30% din cazuri
• Adenom nefuncțional (frecvent)
• Adenocarcinom
• Feocromocitom
• Hiperaldosteronism
• Hiperplazie bilaterală
• TUMORILE TIROIDIENE ASOCIATE MEN1
• 5-30% din cazuri
• Adenom foliculare (frecvent)
• Carcinom tiroidian (exceptional)
NEOPLAZIA ENDOCRINA MULTIPLA (MEN)1
IMAGISTICA IN PanNET
CT: Computed tomography; EGD: Esophagogastroduodenoscopy; EUS: Endoscopic ultrasound; MRI: Magnetic resonance imaging; US: Ultrasound, SRS – somatostatin receptor scintigraphy
Pancreas: CT/MRI, US, EUS, SRS Duodenum: CT/MRI, EUS, SRS
Liver: MRI
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine tumors. V.1.2010. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
EUS
- pana la 90% dintre TU primare
cu localizare pancreatica
- localizeaza TU mici (<0.4 cm)
1. Sherar MD. Imaging in Oncology. In: Tannock IF, Hill RP, Bristow RG, Harrington L (eds). The Basic Science of Oncology. 4th ed. McGraw–Hill; New York, 2005; 2. Metz D, Jensen R. Gastroenterology. 2008;135:1469–92
Ecoendoscopia (EUS)
Scintigrafia Receptorilor
Somatostatinergici (SRS)
Octreoscan
• NET exprima abundent SStRs,
indeosebi SStR-2 si SStR-5
Rezultate fals negative
- tumorile de mici dimensiuni (<1 cm)
- tumorile cu expresie redusa de SStRs,
slab diferentiate
PET/CT
18F-Deoxiglucoza (FDG)-PET
68Ga-DOTATOC (DOTA(0)-
Phe(1)-Tyr(3))octreotid,
Edeotreotid), 68Ga-DOTATATE , 68Ga-DOTANOC
18F-DOPA PET/ CT 5-HTP-
PET/CT
Glucagon-Like Peptide-1
Receptor Imaging (In, Ga)
Tumorile Pituitare in MEN1
• MEN1 – se recomanda screening-ul imagistic si endocrin al tumorilor
hipofizare
• AH secretant de PRL
• AH nefunctional
• AH GH/GH+PRL
Prevalenta crescuta a carcinomului
pituitar in MEN1 - ?
Prevalenta crescuta a AH AGRESIVE
in MEN1
Adenomul Hipofizar “Agresiv/”Invaziv”
• Gr 3 (TU extraselara cu invazia SS, a
sinusului cavernos sau distructie osoasa)
• Gr 4 (TU cu extensie la nivelul SNC sau
extraselara, cu sau fara metastaze)
• Stadiile D si/sau E
• Tumorile infiltrand ≥2/3(67%) din aa carotida
interna – segmentul intracavernos (RMN)
Algoritm de Evaluare Genetica pentru Mutatiile AIP si MEN1 la
Pacienti cu Adenom Hipofizar
Cuny T et al. Eur J Endocrinol 2013;168:533-541
• Gena MEN1 alcătuită din 10 exoni cu o lungime de ≈10kb
• localizată pe braţul lung q al cromozomului 11 (11q13)
• primul exon si o parte din ultimul exon nu sunt traduşi
• MENINA
• proteina intra-nucleara - 610 AA
• supresor tumoral
GENETICA MEN1
Note: Rectangles depict exons. Introns and 5’ and 3’ flanking regions are shown by lines. Arrows show the location and orientation of the primers.
Primer sequence Forward/Reverse Position* PCR product length
(bp)
A: gggtggaaccttagcggaccctgg F 2185-2208 581
B: tcatggatagattcccacctactggg R 2740-2766
C: agggagtgtggcccatcactacctg F 4213-4237 1231
D: ggcccctgcctcagccactgttag R 5421-5444
E: gggcatttgtgccagcagggcagc F 5958-5981 847
F: ctgtccaggtgggaggctggacac R 6782-6805
G: gcctggcctgtgccctctgctaag F 7126-7149 967
H: ggtccccacaagcggtccgaagtc R 8070-8093
* Numbered according to GenBank Acc. No. U93237; F, forward; R, reverse; bp, base pairs.
secventarea regiunii codificatoare
• MUTAŢIA MEN1
• identificată la 70-95% din pacienţii cu sindrom MEN 1
• exonii cel mai frecvent afectati – exonul 2, exonul 10 si exonul 9
• deletii
GENETICA MEN1
MUTATIA MEN1 1670_1672delAGA
exonul 10 al genei la pacient cu MEN1 – aa LYS557
Laboratorul Clinicii Endocrinologie Cluj-Napoca
Ghid Practic de Supraveghere a Subiectilor Testati Pozitiv pentru
Mutatia MEN1 (Brandi et al, J Clin Endocrinol Metab, 2001; Thakker et al, J Clin Endocrinol Metab, 2012]
TEST BIOCHIMIC LOCALIZARE VARSTA INITIERII
SCREENINGULUI
FRECVENTA
TESTARII
PRL si/sau IGF-1 in ser AH
functional 5 ani Anual
Calcemie totala si/sau ionica
si PTH
HPTH
primar 8 ani Anual
Gastrinemie Gastrinom 20 ani Anual
Cg A, PP, glucagon, VIP in
ser
PanNET <10 ani Anual
Glicemie, Insulinemie Insulinom 5 ani Anual
RMN hipofizar AH 5 ani 3-5 ani, in functie
de testele
biochimice
CT/RMN de abdomen PanNET 20 ani 3-5 ani, in functie
de testele
biochimic
CT, RMN de abdomen sau
EndoEcografie
PanNET <10 ani Anual
• MEN2A (prevalenta inalta)
• CARCINOM MEDULAR TIROIDIAN (MTC) (≈100%)
• – debut in etapa de adult tanar
• FEOCROMOCITOM (50%)
• – uni/bilateral, benign/malign
• HIPERPARATIROIDISM (HPTH) PRIMAR (20%)
• – adesea ca hiperplazie difuza a gl paratiroide
• AMILOIDOZA CUTANATA
• BOALA HIRSCHPRUNG
• MEN2B (prevalenta joasa)
• CARCINOM MEDULAR TIROIDIAN (MTC)
• - risc inalt
• - debut in copilarie
• FEOCROMOCITOM
• - risc inalt
• NEURINOAME (linguale, ale buzelor, la nivelul tractului gastrointestinal)
• HABITUS MARFANOID
• LACRIMATIE ABSENTA (80%)
• MTC FAMILIAL • debut in etapa de adult
CLINICA IN NEOPLAZIA ENDOCRINA MULTIPLA (MEN) 2
- prevalenta MEN2 1/35000 cazuri
CANCER TIROIDIAN
5-10% MTC MTC SPORADIC - 75%
MTC FMTC
MEN 2B MEN 2A
MTC = Elementul Clinic Cheie al MEN2
MTC ADP, MTC
Diagnosticul MCT
• US cervicala ± FNAB
• Ultrasonoelastografia
• CT/RMN cervical
• Markerii tumorali
• Calcitonina
• Antigen carcinoembrionar (ACE)
• Testul la Calciu (0.25 mg/kgc) CTser = 11500 pg/mL (<14.3pg/mL)
ACEser = 253 ng/mL (<3.4ng/mL)
Diagnosticul Histopatologic & ImunoHistochimic al MTC
Bifocal MTC of both lobes: stage pT(m)
1bNxMx]. HE staining: (a) 100Å~; (b) 200Å~; (c) 400Å~. Immunohistochemistry: (d) Anti-calcitonin, 200Å~ (e) Anti-CEA, 200Å~; (f)
Anti-TTF-1, 200Å~
Sovrea A, Dronca E, Galatir M, Radian S, Vornicescu C, Georgescu C. Rom J Morphol Embryol, 2014: 389-400
Diagnosticul in Feocromocitom
• Feocromocitomul • 50% dintre cazurile MEN2
• Ac Vandilmandelic
• – sensibilitate 60-65%
• Metanefrinele libere plasmatice
• Metanefrinele urinare fractionate (screening)
• Catecolaminele urinare si plasmatice
• CgA (dg tumorilor nefunctionale)
• Testul de supresie la clonidina • lipsa de supresie a metanefrinelor dupa
clonidina
PCC Immunohistochemistry: (c) Anti-
chromogranin A, 200Å~; (d) Anti-S100, 200Å~.
Negativ:
S100
EMA (Epithelial Membrane
Antigen)
Cytokeratine
Inhibin, CD10, CD31, CD34
Pozitvi:
Chromogranin
Synaptophysin
Vimentin
• CT/RMN abdomino-pelvin
• Scintigrafia cu 123I- sau 131I-
MIBG (metaiodobenzilguanidina)
• PET/CT
• 18F-FDA (fluorodopamina) -
PET
Diagnosticul in Feocromocitom
Genetica MEN2
• Mutatia protooncogenei RET (REarranged during Transfection) la nivelul cromozomului 10q11.21
• 98% din cazurile de MEN2 si 95% din cazurile de FMT
• Proto-oncogena RET
• 80 kb
• 21 exoni
• codeaza un receptor tirozinkinazic transmembranar
mutatie de tip activator stimularea proliferarii celulara si dezvoltare tumorala
• Mutatia genei NTRK1 la nivelul cromozomului 1q21 • – rara
Mutatiile Protooncogenei RET
EXONII
5
8
10
11
13
14
15
16
CODONII
321
515, 533
606, 609, 611, 618, 620
630, 634, 635, 649
768, 776, 790, 791
804, 844
883, 891
912, 918
PROTEINA
RECEPTORULUI
TIROZINKINAZIC
Pedigree of the
MEN2A family.
I – First
generation: I.1 55-year-old
woman (proposita).
II – Second
generation: II.1 37-year-old
affected son; II.2 31-year-old
affected daughter; II.3 26-year
old healthy daughter.
MTC: Medullary thyroid
carcinoma; PCC:
Pheochromocytoma;
(+) Positive for the c.1901G>T
mutation; (-) Negative for the
c.1901G>T mutation.
Sovrea A, Dronca E, Galatir M, Radian S, Vornicescu C, Georgescu C. Rom J Morphol Embryol,
2014: 389-400
MEN2 – Diagnostic Genetic
Electroferograma
codonului 634 al
proto-oncogenei RET
(A) alela “wild-type”
(B) alela mutanta - c.1901G>T
Sovrea A, Dronca E, Galatir M, Radian S, Vornicescu C, Georgescu C. Rom J Morphol Embryol, 2014: 389-400
• Analiza High
Resolution Melting
(HRM) a exonului 11 la
pacienta cu MEN2A
Linii discontinue – probe martor (sanatosi WT si cu
mutatia heterozigota la nivelul codonului 634 (Mut)
Linia punctata – subiect, mutatie absenta
Linie solida – subiect, mutatie prezenta
MEN2 – Diagnostic Genetic
Sovrea A, Dronca E, Galatir M, Radian S, Vornicescu C, Georgescu C. Rom J Morphol Embryol, 2014: 389-400
Corelatii Genotip-Fenotip in MEN2
• prevalenta crescuta a
hiperparatiroidismului
prevalenta crescuta a
feocromocitomului Raue F, Clinics, 2012
in MEN2B – MTC inalt
agresiv, la varsta tanara
MTC cu debut tardiv,
putin agresiv
boala Hirschprung
asociata
amiloidoza asociata
Ghid de Supraveghere a Pacientilor cu Mutatii RET
Patologie codonii
321, 515, 533, 600, 603,
606, 635, 649, 666, 768,
776, 790, 791, 804, 819,
833, 844, 861, 891, 912
codonii
609, 611, 618, 620,
630, 631
codonul
634
codonii
918, 883
MTC Clasa de risc ATA
(2009)
A B C D
Subtipul MEN2 FMTC FMTC/MEN2A MEN2A MEN2B
Agresivitatea MTC Moderata Inalta Inalta Foarte inalta
Varsta la debutul MTC Adult 5 ani < 5 ani < 1 an
Tiroidectomia
profilactica
5 ani, 10 ani sau in
cazul cresterii CT
5 ani < 5 ani In prima luna de
viata
Screening pt
Feocromocitom
> 20 ani, periodic > 20 ani, anual > 8 ani, anual La 8 ani, anual
Screening pt HPTH
> 20 ani, periodic > 20 ani, anual > 8 ani, anual -
Raue F, Frank-Raue K Clinics 2012
MEN 4 (MENX)
• 5-10% dintre pacientii cu sindrom MEN1 clinic, negativi pentru
mutatia genei MEN1
• mutatii la nivelul genei CDNK1B cromozomul 12p13
• codeaza proteina inhibitor a kinazei ciclin-dependente
p27- absenta la pacientii cu MEN4
Terapia specifica a PanNET asociate MEN1
• CHIRURGIA
• curativa (rar), ablativa (frecvent)
• CITOREDUCTIA (“DEBULKING”)
• Ablatia prin radiofrecventa
• Embolizarea/Chemoembolizarea
• TRATAMENTUL MEDICAMENTOS
• Terapia biologica
• Analogii de somatostatina (Octreotide LAR, Lanreotide Autogel)
• Interferonul-α
• Terapia moleculara tintita
• Inhibitorii VEGF-R
• Inhibitorii mTOR
• Alti inhibitori ai tirozinkinazelor (TKI)
• RADIOTERAPIA
• Externa (metastaze)
• Radioterapia tintita (90Y, 177L
Obiectiv primar: PFS p progression-free survival (ITT population, N=204)
0 3 6 9 12 18 24 27
0
10
20
30
40
50
60
70
80
90
100
Pac
ien
ti s
up
rav
ietu
ito
ri, fa
ra p
rog
resi
e tu
mo
rala
Luni
62%
22%
Lanreotide Autogel vs placebo
p = 0.0002, HR = 0.47 (95% CI: 0.30, 0.73)
Caplin M, et al. LBA3 Eur J Cancer 2013;49 (supp 3). Presented at ECCO-ESMO 2103
scadere cu 53% a riscului
de progresie tumorala
Analogii de Somatostatina in Terapia PanNet - Studiul CLARINET
N = 204
• GEP-NET inalt sau moderat diferentiate Nefunctionale
Subgroup Analysis (ITT): Midgut vs. pNET
Caplin M, et al. LBA3 Eur J Cancer 2013;49 (supp 3). Presented at ECCO-ESMO 2103
HR, hazard ratio; ITT, intention-to-treat; NC, not calculable. p value derived from log-rank test, HR derived from Cox proportional hazard model
0 3 6 9 12 18 24 27
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts a
liv
e an
d w
ith
no
pro
gre
ssio
n (
%)
Lanreotide Autogel 120 mg
Midgut NETs (n = 73)
Lanreotide Autogel vs placebo
p = 0.0091, HR = 0.35 (95% CI: 0.16, 0.80)
0
10
20
30
40
50
60
70
80
90
100
Luni
Lanreotide Autogel 120 mg
PanNET (n = 91)
Lanreotide Autogel vs placebo
p = 0.0637, HR = 0.58 (95% CI: 0.32, 1.04)
0 3 6 9 12 18 24 27
Luni
Ghid Terapeutic al Pacientilor cu MTC
• MTC – Tiroidectomie totala cu disectie ganglionara extinsa • tiroidectomie profilactica la pacientii identificati pozitiv pentru mutatia protooncogenei
RET
• obligatoriu - screeningul preoperator al feocromocitomului
• supraveghere anuala (sau adaptata) biochimica (CT) in vederea decelarii bolii reziduale
sau recurente
• Radioterapia si Chimioterapia (ciclofosfamida, vincristina etc) – in boala metastatica si
nerezecabila
• Inhibitorii receptorilor tirozin-kinazei (TKI) – MTC evolutiv, nerezecabil local si/sau metastatic
• Vandetanib (Caprelsa®)
• Cabozantinib (Cometriq®) 60-140 mg/zi
• Sunitinib (Sutent®)
Reactii adverse ale TKI – >10% din cazuri - stomatita, diaree, fatigabilitate, disgeuzie, HTA
- rar - criza HTA, hemoragii, leucoencefalopatie
• Inhibitorii caii mTOR • Everolimus (Afinitor®)
Ghid Terapeutic al Pacientilor cu MTC
Concluzii
• Sindroamele MEN – afectiuni cu transmitere genetica, AD,
care impun masuri de screening genetic la nivelul tuturor
membrilor unei familii avand cazul index testat genetic
pozitiv
• Sindromul MEN2 recunoaste corelatii genotip-fenotip bine
caracterizate, in opozitie cu sindromul MEN1
Concluzii
• Elementul de gravitate in sindromul MEN1 este
reprezentat de potentialul malign al NET pancreatice
• Elementul de gravitate in sindromul MEN2 este reprezentat
de agresivitatea MTC
•
• Evaluarea, managementul si monitorizarea pacientilor cu
sindroame MEN impune existenta unor ghiduri si
protocoale specifice.