Il feocromocitoma
nella
Sindrome di Von Hippel Lindau
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
Feocromocitoma
Ipersecrezione di
catecolamine
Ipertensione arteriosa:
•
•
•
parossistica
intermittente
continua
Anomalie metaboliche:
• aumento M.B.
(intolleranza al caldo,
calo ponderale)
• ridotta tolleranza
glucidica (raro diabete
conclamato)
Altri sintomi:
•
•
Comuni:
cefalea, tachicardia, iperidrosi
(triade classica nel 15-24% dei casi; singolarmente ciascuno nel 70% dei casi)
Rari:
dolore addominale/toracico, diarrea, vomito, astenia, disturbi accomodazione
Caratteristiche del Feocromocitoma nel VHL
Età alla diagnosi
28
Fenotipo:
noradrenergico
Ipertensione:
continua/assente
Crisi ipertensive:
rare
N.B. ad oggi non ci sono prove istologiche di
MNs plasmatiche:
normetanefrine
malignità ma l’unico criterio accettato di
Secrezione CA:
continua
malignità è la presenza di metastasi !
E’Prevalenza
ancoranella
piùSdr
importante
saper
distinguere
VHL:
20-25%
tra metastasi e malattia multifocale
!!!
Bilateralità:
40%
Localizzazione extra-surrenalica:
2-11%
Frequenza di malignità:
5%
Opocher G. et al. Familial Cancer 2005; 4:13-16.
Referto Istologico
PASS
Pheochromocytoma of the Adrenal gland Scoring Scale
Il PASS può indicarmi un feocromocitoma a
comportamento potenzialmente aggressivo
(se ≥ 4/20) ma non è diagnostico di malignità.
(E viceversa…..)
Thompson L.D.R. Am J Surg Pathol 2002;26:551-566
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
NATURE CLINICAL PRACTICE
ENDOCRINOLOGY & METABOLISM
FEBRUARY 2007 VOL 3 PAG 92-102
BIOCHEMICAL DIAGNOSIS
Recommendations
Pheochromocytomas and extra-adrenal paragangliomas are 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.
Measurement of urinary 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
metanephrine measured separately) in urine or plasma provide superior
diagnostic sensitivity to measurements of the parent catecholamines.
Lenders JW et al. Lancet 2005; 366:665-75.
Interferenze su dosaggi catecolamine e metaboliti
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.
NATURE CLINICAL PRACTICE
ENDOCRINOLOGY & METABOLISM
FEBRUARY 2007 VOL 3 PAG 92-102
Recommendations
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.
1.
If suspicion is derived from signs and symptoms of catecholamine
excess, biochemical test results should be strongly positive.
2.
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.
NATURE CLINICAL PRACTICE
ENDOCRINOLOGY & METABOLISM
FEBRUARY 2007 VOL 3 PAG 92-102
TC o RMN?
… 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.
NATURE CLINICAL PRACTICE
ENDOCRINOLOGY & METABOLISM
FEBRUARY 2007 VOL 3 PAG 92-102
Scintigrafia
MIBG
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
pheochromocytomas or paragangliomas from other lesions;
• 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.
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 feocromocitoma e almeno 7-14 giorni
prima dell’intervento chirurgico.
Gli -antagonisti
localizzazione.
non
interferiscono
con
le
metodiche
di
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
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
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
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)
= Metirosina,
inibitore competitivo
della sintesi catecolamine
Pacak K. JCEM 2007;92:4069-4079
Algoritmo del trattamento pre-operatorio
Follow-up
Nel paziente VHL: ABPM, metanefrine
urinarie, CGA e RMN addome 1
volta/anno ogni anno
Nel feocromocitoma sporadico: diario
pressorio, CGA e metanefrine urinarie 1
volta/anno per 10 anni
Grazie per l’attenzione