Carcino M timic secretant de ACTH – caz clinic

1. CarcinoMtimicsecretant de ACTH – caz clinic Dr Maria-Christina Ungureanu

2. JUN 2008 GCM 35 ani Aspect clinic cushigoid: facies in lunaplina, ceafa de bizon, obezitatefacio-tronculara, hirsutism, amenoreesecundara • HTA 160/90mmHG • HGPO T0h 116 T2h 237 • K 2.3 mmol/l • Na 148 mmol/l • RA 41mmol/l

3. Cortizolora 8: 582mg/dl (50-230) Cortizolora 23: 590mg/dl (30-130) CLU532/24h Test DXM 1mg over night 598ng/dl Test DXM 8 mg over night 287 ng/dl ACTH292pg/ml (<46) Echografietiroidiana aspect normal Calcitonina 5 ng/ml Rgftorace – ITN Echografiaabdominala, CT abdominal:infirma o tumora cu localizarepancreaticasauintestinala, aspect normal al GSR RMN cranian: aspect normal

4. CT toracic formatiuneexpansiva de 34/42/49 mm cu discrete calcificarisipriza de contrast, cu contact larg cu pericardul in sectiuneaperivasculara, absentaadenopatiilormediastinale

5. 3 JUL 2008 Ablatiaformatiuniitumorala cu rezectie de pericardsi pleura stg Anat-pat: Carcinomneuroendocrintimicbinediferentiat T2NxMx Imunhistochimie: NSE intenspozitiv; chromograninpozitivdifuz in tumora; synaptophisinpozitivintensdifuz Ki6710% in celtumorale

6. 28.07.08 - postoperator TA = 120/75mmHG Na=142 mmol/l     K=4.0 mmol/l RAlc =22 mmol/l   ciclu glicemic88 -108 mg/-127 mg/dL  -96 mg/-93 mg/dl Cortizolul plasmatic: Ora 8: 97,4 ng/ml (preoperator 582 ng/ml) Ora 23: 3,9 ng/ml (preoperator 590 ng/ml ). CLU 178,9 mg/24 h (preoperator 532 mg/24 h) ACTH plasmatic 37 pg/ml (preoperator 292 pg/ml) testosteronului plasmatic 0,1 ng/ml DHEAS 0,3 ng/ml.

7. AMENOREICA:  Duphaston 2 cp/zi, 10 zile pe luna DMO scazut Cal D Vita 2 cp/zi, Bonviva 1 cp/luna control la 3 luni in postoperator pentru reevaluare imagistica si a markerilor tumorali, cu bilet de trimitere.

8. 06.07.09 o discreta hiperpigmentare fara alte semne fizice caracteristice sdr Cushing cortizol 8,00 - 221 ng/ml(50-230) cortizol 23,00 - 123,7 ng/ml (30-130) ACTH 88 pg/ml test la DxM la 1 mg : cortizol 231 Test DXM 8 mg cortizol 235 ng/ml CT mediastinal nu releva recidiva la acest nivel Nu se constata leziuni expansive la echo abdominala si tiroidiana. DMO dupa interventia chirurgicala s-a ameliorat de la -2,4 la -1,6.

9. 15.09.09 CT toracic • suspiciune de recidiva tumorala la nivelul pachetului mamar intern stg in portiunea superioara - form. de 18/11 mm cu aspect polici clic relativ bine conturat. Se ridica suspiciunea unei adenopatii situata intern si posterior de vena renala stg.

10. tratament cu Nizoral 800mg/zi sub care a dezvoltat sdr alergic cutanat • reinterventie chirurgicala conform programarii urmata de tratament cu analogi de somatostatin

11. Nu se prezinta la operatie

12. Nov 2009 - Contactatatelefonic • 2 cure CHT - carboplatin si etoposid • recomadare sandostatin LAR • dosar inaintat de oncologul din Bacau – tratament initiat nov/dec 2009 Ian 2010 - HTA necontrolata medicamentos

13. 01.10 cortizol plasmatic ora 8.00: 320 ng/m (50-230) test overnight 1 mg DxM – cortizol: 292,8 ng/ml test overnight 8 mg DxM – cortizol: 290,3 ng/ml testosteron plasmatic: 3 ng/ml HGPO: 129 - 284 mg/dl  - 355 mg/dl     Cromogranina A 97ug/L (27-94) Oct 2009– 480ug/L

14. CT toracic adenopatii mamare interne stingi (aspect stationar fata de examinarea precedenta - 09.2009) dar si leziuni secundare osoase osteosclerozante corpi vertebrali C7 si L1 (22/10 mm respectiv 25/25 mm). Sunt absente elementele CT sugestive pentru recidiva locala la nivelul lojei timice.

15. 25.01.10 12:29 :   Na*=140 mmol/l     , K*=2.01 mmol/l     , REZERVA ALCALINA*=37.4 mmol/L           26.01.10 10:22 :   Na*=143 mmol/l     , K*=1.90 mmol/l     26.01.10 17:24 :   Na*=140 mmol/l     , K*=2.08 mmol/l     27.01.10 07:55 :   K*=2.37 mmol/l     , REZERVA ALCALINA*=41.5 mmol/L         27.01.10 18:19 :   Na*=143 mmol/l     , K*=2.2 mmol/l     ,      , REZERVA ALCALINA*=41 mmol/L     28.01.10 06:15 :   Na*=144 mmol/l     , K*=3.02 mmol/l     , Cl*=88.3 mmol/l     , REZERVA ALCALINA*=44.2 mmol/L     28.01.10 18:24 :   K*=3.8 mmol/l     29.01.10 09:20 :   K*=3.98 mmol/l     , REZERVA ALCALINA*=37.1 mmol/L         , REZERVA ALCALINA*=31.6 mmol/L     31.01.10 08:49 :   K*=5.20 mmol/l     , REZERVA ALCALINA*=30.9 mmol/L     31.01.10 17:54 :   K*=4.9 mmol/l     , REZERVA ALCALINA*=28.7 mmol/L     01.02.10 07:52 :   Na=141 mmol/l     , K=3.30 mmol/l  , R. ALC = 29.2 mmol/L   sub 200 mg spironolactona/zisi 3 g KCl/zip.o

16. Transferata Chrirurgie pt adrenalectomie bilaterala K 1.7mmol/l Infarct miocardic posterior Decedeaza 5.02.2010 – Fibrilatie ventriculara

17. Carcinoameletimice Incidenta TNE – 5.25/100 000/an Yao: J Clin Oncol 2008 Carcinoideletimice0.02/100 000/an Sub 5% din neoplasmelemediastinaleanterioare Raportbarbati:femei3:1 Virstamedie de dg – 59 ani Imunohistochimicpozitive pt neuron-specific enolase, chromogranin A, somatostatin, synaptophysinesi CD56 Cuiburicelulare cu arii de necroza Chaer: The Annals of Thoracic Surgery 2002, O’ berg: Annals of Oncology 2010

18. Carcinoameletimice Tumori cu grad redus(<10 mitozepe 10 cimpuri) de malignitate intermediar, inalt (>10 mitoze /10 cimpuri) Supravietuire pt tumtimice cu grad redus50% la 5 anisi 9% la 10 ani cu grad inaltsupravietuirea la 5 ani e 0 • Chaer: The Annals of Thoracic Surgery 2002, O¨ berg: Annals of Oncology 2010

19. Manifestariclinice: • Asimtomatice • Simtome de compresiunetoracica • Sdrendocrin • Semnesisimtome a unei MTS la distanta (ficat, plamin, pancreas, pleura, os) Chaer: The Annals of Thoracic Surgery 2002, O¨ berg: Annals of Oncology 2010

20. NVSDR CUSHING ECTOPIC

21. Carcinoidelesecretante de ACTH/CRH Carcinoidelesecr ACTH – incidenta 1-2 cazuri la 100 000 locuitori Secretiaectopica de ACTH apare in 10-20% din sdr Cushing endogene Cuprinde: • cancerulpulmonar cu celulemici • carcinoidelebronsice, intestinalesipancreatice • CMT • feocromocitoamelesiparaganglioamele, • carcinoame – hipernefroamele, cancerul de colon

22. Distribution of the most frequent source (> 2%) of ectopic ACTH secretion in a group of 383 patients with EAS syndrome based on the following published series: Aniszewski et al, Findling et al., Imura et al., Doppman et al., Howlett et al., Ilias et al., Isidori et al., Salgado et al.. Isidori: Arq Bras Endocrinol Metab 2007

23. Distribution of the most frequent source (> 2%) of ectopic ACTH secretion in a group of 383 patients with EAS syndrome based on the following published series: Aniszewski et al, Findling et al., Imura et al., Doppman et al., Howlett et al., Ilias et al., Isidori et al., Salgado et al.. Isidori: Arq Bras Endocrinol Metab 2007

24. Sursaneidentificata 12,5% NIH -19% ( Ilias: JCEM 2005 , Isidori : JCEM 2006)

25. Clinic • Tumori agresive – tabloul clinic de Cushing mai putin evident • Tumori neuroendocrine bine diferentiate cu evolutie lenta – dezvoltarea completa a semnelor de hipercortizolism: • Hiperpigmentatia – 67% • Acnee – 69% • Edeme mb inf 67% • Astenie musculara 69% • Manifestari psihice – 65% • HTA 44% Tabarin:JCEM 1996

26. 90 pacienti cu Cushing ectopic • Astenie musculara74 / 90 (82%) • Crestere in greutate 64 / 90 (70%) • HTA 70 / 90 (78%) • Tulb menstruale 28 / 36 (78%) • Hirsutism 36 / 48 (75%) • Osteopenia / osteoporoza27 / 36 (75%) • Hipokalemia 64 / 90 (71%) • Tulb psihice 48 / 90 (53%) • Infectii46 / 90 (51%) • Diabet 45 / 90 (50%) • Striuri purpurice 40 / 90 (44%) • Obezitate faciotronculara35 / 90 (39%) • Edeme 34 / 90 (38%) Cushing’s Syndrome Due To Ectopic Corticotropin Secretion: Twenty Years’ Experience At The NIHIoannisIlias, et al In JCEM 2005

27. DIAGNOSTIC HORMONAL • dozareacortizoluluisi a ACTH-uluibazal • testele de supresie cu DXM (! Carcinoidebronsice) • Testul la CRH– rasp (-) in tumorileadrenalesiectopice • Testul la ACTH- rasp (+) in formele ACTH dep • Cateterismul de sinus petrosinf– considerat gold standard in dg Cushing ectopic • Altimarkericaracteristici TNE chromogranina A(CgA), serotonina, ac 5HIA, neuron-specific enolase (NSE), achaete-scute homolog 1 (ASCL1) synaptophysin (P38), calcitonina, kalikreina, glucagon , gastrina • Testul de supresie la somatostatin– scadereala jumatate a nivelului ACTH la 4-6 ore de la inj a 100ug Sandostatin; recomandat pt selectiapacientilorce pot beneficia de sintigrafia cu Octreotid (Masaru, Endocrine J 2008)

28. Imagistica • radiografiasimpla • echografiaabdominalasicervicala ant • CT: • State-of-the-art multidetector CT: achizitionarea a 8 , 6, or 24 felii/sec. Se recom CT seriat de la virfulpulmonilorpina la cresteleiliace la dist de 2.5mm dupainjectareasubst de contrast (Isidori : JCEM 2006) • RMN • Scintigrama cu In-111 pentetreotide ( Octreoscan) • Nu identificaleziunice nu pot fiobservate la CT, sezitivitate 49% (Ilias JCEM 2005) • I-131 sau I-123 – MIBG (metaiodobenzylguanidine) -pentrutumorile din medularaadrenalasau cu celcromafine • PET si SPECT cu 11C-5HTP (hydroxy tryptophan)sau18F-FDOPA PET ([18F]fluoro-dihydroxyphenylalanine positron emission tomography) (maibunadecit cu glucozadatactvmetabreduse a TNE) (Becherer: 2004 J of Nuclear Medicine, Kauhanen1, Endocrine Ralated Cancer 2009)

29. TRATAMENT Obiective • Indepartarea tumorii primare • Ameliorarea simptomelor • Controlul cresterii tumorale si a metastazelor • Ameliorarea calitatii vietii pacientului

30. Tratamentultumoriiprimaresi a metastazelor • Rezectietotala/partiala a tumoriiprimare tratamentcurativ :12% (Mayo clinic) - 29% (NIH) • Rezectiametastazelor • Iradiereexterna (carcinoamelepulm) • Tratamentendobronsic cu laser • Chemoembolizarea • Ablatiaprinradiofrecventa KaltsasClinEndocrinol (Oxf). 2002, Ilias JCEM 2005, O¨ berg: Annals of Oncology 2010

31. Tratamentultumoriiprimaresi a metastazelor • Chimioterapiaexterna:cisplatin, etoposide, streptozotocin (SZT), 5-fluorouracil (5-FU), adryamicine • Interferon alpha • Temozolomide, Sunitimib (inhibitori de tirosine-kinase), Bevacizumab (inhibitor de VEGF) sau m-TOR inhibitori(Everolimus) are o rata de raspuns de 10%–15% non-funct • Hormone-delivered radiotherapy/ peptide receptor radionuclide therapy  – PRRT (radioterapiemetabolica) - pentrutumorile cu receptoripentrusandostatin (micsorare >50% din cazuri) utlizeaza ca radionuclidindium-111, lutetium-177 sicelmaiputernicyttrium-90 KaltsasClinEndocrinol (Oxf). 2002, Ilias JCEM 2005, O¨ berg: Annals of Oncology 2010

32. Tratmentulexcesului de glucocorticoizi Inhibitoriaisecretiei de glucocorticoizi: • Ketoknazolul 200mg X 2/zipina la 1600mg/zi • Metyrapon– nu la fel de eficient ca Ketokonazolul, poatedeterminahipokalemie 250mg x 4/zi maxim 6000mg/zi (Divakar Yale University, Oct-2010) • Mifepriston – fara un control adecvat al hipokalemiei (Cassier Ph, Eur J of Endocrinology (2008) • Etomidate in perfuzie Adrenalectomie Necesara in 30-37% din cazuri Ilias: JCEM 2005, Isidori : JCEM 2006

33. tratamentulsecretieiexcesive de acth de la nivelultumoriiprimaresi a mts • Analogi de somatostatina (Octreotid, Lanreotid, Pasireotide) • Octreotide/ Pasireotid + • Everolimus(RAD001 ) TNE pancreatice • Octreotide+ Everolimus + Bevacizumab • Octreotid+ interferon alpha in carcinoidelepancreatice • Cabergolina(7mg/sapt) • Analogi de somatostatin + cabergolina in b cushingdarsisdr Cushing ectopic Pivonello, N Engl J Med 2005;

34. Urmarire Minim 10 ani determinareachromograninei/ profilului hormonal la 3-6 luni; CT/RMN anual maifrecvent in caz de MTS saurecidiva

35. EVOLUTIE, PROGNOSTICCarcinoideletimice Chaer: The Annals of Thoracic Surgery 2002

36. Evolutie, PrognosticCarcinoideletimice Din 108 pacienti cu carcinoidetimice 51% au avut o supravietuire de 3 ani 27% - 5 ani 9% > 10 ani Celeneinsotite de simptendocrina – mortalitate 30% in 5 ani Asociate cu sdr Cushing sau MENI – mortalitate 65% in 5 ani Chaer: The Annals of Thoracic Surgery 2002

37. Evolutie, Prognostic Tumorile cu secretieectopica de ACTH • Carcinoidelebronsice au celmai bun prognostic • Tumoriletimicesifeocromocitoamele – prognostic intermediar • Tumorilepancreaticesi CMT suntagresivesiadesea cu MTS in momentul dg • Ca pulm cu celmici – prognosticulcelmaiprost (6-8luni) • Tumorileoculte cu un bun control al hipercortizolismului – prognostic bun • Marimeatumorii nu se coreleaza cu severitateasimptomeloriarnivelul ACTH nu se coreleaza cu agresivitateasa (Isidori : JCEM 2006)

38. Tumorileextratoracice, carcinoideletimice, SCLC, CMT sigastrinoamele au un prognostic prost cu supavietuire in medie 24.2 luni. Pacientii cu surse de ACTH ocultesaunecunoscute au un prognostic mai bun. Pacientii cu tumoripulmonare (exceptind SCLC au progosticulcelmai bun) Ilias: JCEM 2005

39. Histologiatumoralasiprezentametastazelorsuntceimaiimportantifactoriprognosticipentrusupravietuire (P< 0.05) Isidori : JCEM 2006

41. radiolog chirurg Chimioterapice rezectie Anti cortizolice anticortizolice