Il feocromocitoma nella Sindrome di Von Hippel Lindau

1. Ilfeocromocitoma nella Sindromedi Von HippelLindau

2. Von Hippel-Lindau syndrome: Type 1 (no pheochromocytoma) Renal cell carcinomas Retinal and central nervous system haemangioblastomas Pancreatic neoplasms and cysts Type 2 (with pheochromocytoma) 2A: Retinal and central nervous system haemangioblastomas Pheochromocytomas 2B: Renal cell carcinomas Retinal and central nervous system haemangioblastomas Pancreatic neoplasms and cysts Pheochromocytomas 2C: Pheochromocytomas only Lancet. 2005 Aug 20-26;366(9486):665-75

3. Ipersecrezione di catecolamine • Ipertensionearteriosa: • parossistica • intermittente • continua Anomalie metaboliche: • aumento M.B. (intolleranza al caldo, calo ponderale) • ridotta tolleranza glucidica (raro diabete conclamato) Feocromocitoma Altrisintomi: • Comuni: • cefalea, tachicardia, iperidrosi • (triadeclassicanel 15-24% deicasi; singolarmenteciascunonel 70% deicasi) • Rari: • doloreaddominale/toracico, diarrea, vomito, astenia, disturbiaccomodazione

4. Caratteristiche del Feocromocitoma nel VHL • Età alla diagnosi28 Fenotipo: noradrenergico MNs plasmatiche:normetanefrine Secrezione CA: continua Ipertensione: continua/assente Crisi ipertensive: rare Prevalenza nella Sdr VHL: 20-25% Bilateralità: 40% Localizzazione extra-surrenalica: 2-11% Frequenza di malignità: 5% N.B. ad oggi non ci sono prove istologiche di malignità ma l’unico criterio accettato di malignità è la presenza di metastasi ! E’ ancora più importante saper distinguere trametastasiemalattia multifocale!!! Opocher G. et al. Familial Cancer 2005; 4:13-16.

5. Referto Istologico

6. PASS Pheochromocytomaof the AdrenalglandScoring Scale IlPASS può indicarmi un feocromocitoma a comportamento potenzialmente aggressivo (se ≥ 4/20) manon è diagnostico di malignità. (E viceversa…..) Thompson L.D.R. Am J Surg Pathol 2002;26:551-566

7. Diagnosis Elevated free catecholamine excretion or high levels of metabolites (that is, metanephrines or vanillylmandelic acid [VMA]) in the serum or urine establish the diagnosis of pheochromocytoma… Recommended biochemical tests for diagnosis of pheochromocytoma include the following: • Plasma free metanephrines. The plasma free metanephrine concentration is a highly sensitive test but is considerably less specific than 24-hour urine collection for free metanephrines or VMA. If normal levels are detected, the presence of a neoplasm of the sympathetic nervous system is highly unlikely. • Timed urine collection (minimum of 4 hours) for metanephrines. These assays are most effective when performed during or immediately after a symptomatic episode. • Urine collection (24-hour specimen) for free catecholamines, metanephrines, and VMA. Urinary VMA is the most specific of all tests for the diagnosis of pheochromocytoma. L.G. AACE 2006 AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF HYPERTENSION ENDOCRINE PRACTICE Vol 12 No. 2 March/April 2006 193

8. Recommendations NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM FEBRUARY 2007 VOL 3 PAG 92-102 BIOCHEMICAL DIAGNOSIS Pheochromocytomas and extra-adrenalparagangliomasare rare, and often overlooked, causes of hypertension. The crucial first step is therefore to consider these tumors when thinking of possible diagnoses. Confirming the diagnosis requires biochemical evidence of inappropriate catecholamine production. Measurementofurinary catecholamine levels has traditionally been the most widely used test, but measurement of urinary catecholamine metabolites or plasma catecholamines has also been recommended… studies have confirmed that measurements of fractionated metanephrines(i.e. normetanephrine and metanephrinemeasuredseparately) in urine or plasma provide superior diagnostic sensitivity to measurements of the parentcatecholamines.

9. Interferenze su dosaggi catecolamine e metaboliti Lenders JW et al. Lancet 2005; 366:665-75.

10. CGA Conclusions: Plasma determinations of metanephrines are now an easy and convenient tool for the diagnosis of pheochromocytoma. However, in our study the best specificity was obtained with the urinary tests rather than with the plasma assays while the highest sensitivities were for the normetanephrine assays. The assay of CgA was highly efficient in diagnosing pheochromocytomas in the absence of renal insufficiency. By combining it with fractionated metanephrine assays, the sensitivities of the latter were increased.

11. Recommendations NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM FEBRUARY 2007 VOL 3 PAG 92-102 TUMOR LOCALIZATION The panel of experts at the ISP felt strongly that localization of pheochromocytoma or paraganglioma should only be initiated if the clinical evidence for the presence of tumor is reasonably compelling. • If suspicion is derived from signs and symptoms of catecholamine excess, biochemical test results should be strongly positive. • If the pretest probability of a tumor is higher, such as in patients with a hereditary predisposition or previous history of the tumor, less compelling biochemical evidence might justify imaging studies.

12. TC o RMN? NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM FEBRUARY 2007 VOL 3 PAG 92-102 … there was no consensus on whether CT or MRI is preferred for initial localization of a tumor. This largely depends on the institutional preference and local expertise. Regardless of whether CT or MRI is used, there was a general agreement that imaging studies should initially focus on the abdomen and pelvis. If a tumor is not found, chest and neck images should be obtained, but with recognition that metastatic lesions in long bones can be missed. Although CT and MRI have excellent sensitivity for detecting most catecholamine-producing tumors,these anatomic imaging approaches lack the specificity required to unequivocally identify a mass as a pheochromocytoma or paraganglioma.

13. Scintigrafia MIBG NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM FEBRUARY 2007 VOL 3 PAG 92-102 The panel of experts agreed that functional imaging is useful. The test of choice is currently 123I-labeled meta-iodobenzylguanide (MIBG) scintigraphy. Two main reasons warrant the use of functional imaging: • first, the modality provides a method to more correctly distinguish pheochromocytomasor paragangliomasfromotherlesions; • second, it enables determination of the extent of disease, including the presence of multiple tumors or metastases. Exceptions for which functional imaging might not be required include adrenal tumors of <5 cm in diameter that are associated with a significant elevation of plasma or urine metanephrine levels.

14. TERAPIA MEDICA DEL FEOCROMOCITOMA La terapia medica del Feocromocitoma si basa sull’uso degli -antagonisti La terapia medica deve essere iniziata appena i dati di laboratorio dimostrano la presenza del feocromocitomae almeno 7-14 giorni prima dell’intervento chirurgico. Gli -antagonisti non interferiscono con le metodiche di localizzazione. Si può associare un β-bloccante (meglio se β1-selettivo come atenololo o metoprololo) solo dopo almeno 2 giorni di terapia con -antagonisti Lenders JW et al. Lancet 2005;366:665-75 Pacak K. JCEM 2007;92:4069-4079

15. Preparazione all’intervento chirurgico La terapia -litica: Riduce la pressione arteriosa Riduce le crisi ipertensive Riespande il volume plasmatico Annulla gli effetti della downregulation Elimina la crisi ipotensiva post-operatoria Terapia per os: Fenossibenzamina (non in commercio in Italia) Doxazosina

16. DOXAZOSINA Inibitore competitivo Inibitore selettivo alfa1 Cp da 2 o 4 mg; in commercio in Italia Emivita: 20 h Dose: 4-16 mg/die in 3-6 somministrazioni Effetti collaterali: ipotensione ortostatica

17. Calcio antagonisti Bloccano l’ingresso di calcio NA-mediato nelle cellule muscolari lisce vasali • Da associare nei pazienti con controllo pressorio inadeguato, per evitare l’aumento di posologia dell’alfa-litico e i suoi effetti collaterali. • In sostituzione dei bloccanti dei recettori adrenergici in pazienti con importanti effetti collaterali. • Per prevenire l’ipotensione ortostatica iatrogena in pazienti con ipertensione intermittente. • Per prevenire lo spasmo coronarico indotto dall’eccesso di catecolamine. Più utilizzati: amlodipina 10-20 mg die (Norvasc) nicardipina 60-90 mg die (Nicapress) nifedipina 30-90 mg die (Adalat) verapamil 180-540 mg die (Isoptin)

18. Algoritmo del trattamento pre-operatorio = Metirosina, inibitore competitivo della sintesi catecolamine Pacak K. JCEM 2007;92:4069-4079

19. Follow-up Nel feocromocitoma sporadico: diario pressorio, CGA e metanefrine urinarie 1 volta/anno per 10 anni Nel paziente VHL: ABPM, metanefrine urinarie, CGA e RMN addome 1 volta/anno ogni anno

20. Grazie per l’attenzione