PROF. FRANCESCO GIORGINO
DIPARTIMENTO DELL’EMERGENZA
E DEI TRAPIANTI DI ORGANI
SEZIONE DI MEDICINA INTERNA, ENDOCRINOLOGIA,
ANDROLOGIA E MALATTIE METABOLICHE
• “incidentaloma” - mass lesions discovered
serendipitously during an imaging investigation.
• Endocrine glands (pituitary, thyroid, parathyroid and
adrenal) represent the organs that most commonly
harbor incidentally discovered lesions.
Vassiliadi, D. A. & Tsagarakis, S. Nat. Rev. Endocrinol. 7, 668–680 (2011);
Kloos, R. T., Gross, M. D., Francis, I. R.,
Korobkin, M. & Shapiro, B. Incidentally
discovered adrenal masses. Endocr. Rev.
16, 460–484 (1995).
Adrenal lesions are bilateral in 8–17% of cases in radiological
studies76–78 and 20% in autopsy studies. In one autopsy study
that considered lesions <2 mm, bilateral nodularity was seen in 19
of the 21 cases in which both glands were examined.

An adrenal incidentaloma is a mass lesion greater than 1
cm in diameter, serendipitously discovered by radiologic
examination.
Discovery of an adrenal mass raises 3 questions that
determine the degree of evaluation and the need for
therapy:
1. Is the tumor hormonally active?
2. Does it have radiologic features of malignant lesion?
3. Does the patient have a history of previous malignancy?

Corticosurrene
Midollare
Adenoma
Feocromocitoma Mielolipoma
Iperplasia
nodulare
Ganglioneuroma
Ganglioneuroblastoma
Carcinoma
Altre masse
Neurofibroma
Amartoma
Teratoma
Xantomatosi
Amiloidosi
Cisti
Ematoma
Granulomatosi
Metastasi
Carcinoma
mammario
Carcinoma
polmonare
Linfoma
Leucemia
Altri
“Is it malignant?”
 Metastases in the adrenals are common.
 In oncologic patients up to 20% and 40% of adrenal
incidentalomas are metastasis in radiology and post-mortem
cohorts, respectively (Barzon L et al, Eur. J. Endocrinol. 2003).
 Adrenal cortical carcinoma is rare (2.5-9.0%, surgical series;
1.4%, unselected patients), but shows high mortality rate
(Barzon L et al, Eur. J. Endocrinol. 2003; Cawood T J et al, Eur. J.
Endocrinol. 2009).
Adenomas 52%
Carcinomas 12%
Mantero F et al, J Clin Endocrinol & Metab, 2000
Others 8%
Pheo
11%
3 rare types of nodular adrenocortical
diseases that are usually bilateral:
ACTH-dependent bilateral macronodular
hyperplasia secondary to long-term adrenal
stimulation in patients with Cushing's disease
(pituitary ACTH-secreting tumor) or ectopic
ACTH syndrome
ACTH-independent bilateral macronodular
adrenal hyperplasia (AIMAH)
Due to aberrant adrenal expression of ectopic or
increased activity of eutopic peptide hormone
receptors (GIP, vasopressin, beta-adrenergic,
LH/hCG, serotonin, and angiotensin receptors)
ACTH-independent micronodular hyperplasia
or dysplasia and its most frequent variant,
primary pigmented nodular adrenocortical
disease (PPNAD)
May be sporadic or familial (as part of the Carney
complex, due to PRKAR1A, PDE11A, PDE8B, and
MYH8 gene mutations)
Tumor size
Adrenocortical carcinoma
<4 cm
2%
4.1-6.0 cm
6%
>6 cm
25%
Mantero F et al, J Clin Endocrinol & Metab, 2000
Mansmann et al, Endocr Rev, 2004
“Is it functioning?”
 The possible presence of a functioning mass is often
suggested by the history (e.g., palpitations, sweating, or
headache [Pheocromocytoma]), physical examination (e.g.,
features of Cushing's syndrome, hypertension, virilization
[Androgen-secreting tumors]), and routine laboratory
findings (e.g., hypokalemia [Primary aldosteronism]).
 Subclinical hormone overproduction by incidentalomas may
be associated with increased morbidity.
“The presence of an inapparent adrenal mass does not
mean absence of endocrine activity.
The patient with an adrenal mass requires a complete
history and physical examination, biochemical evaluation of
all pertinent hormones, and possibly additional radiological
studies.”
Mansmann et al, Endocr Rev, 2004
PREVALENZA DI PATOLOGIA:
analisi del Gruppo di Studio Italiano
sugli Incidentalomi Surrenalici (1004 pazienti)
6%
3% 1%
90%
Adenomi non secernenti
Adenomi con sindrome di pre-Cushing
Feocromocitomi
Aldosteronomi
Mantero F et al, J Clin Endocrinol & Metab, 2000
La Sindrome di
Cushing
Obesità tronculare,
gibbo di bufalo
Faccia a “luna piena”
Ipertensione arteriosa
Intolleranza glicidica, diabete
Irsutismo, acne
Disfunzioni sessuali:
Amenorrea
Impotenza
Osteoporosi, Rachialgie
Calcolosi renale
Astenia muscolare
Strie purpuree
Fragilità vasale, ecchimosi
Alterazioni psichiche
Scompenso cardiaco
Subclinical Cushing Syndrome (SCS)
Subclinical Autonomous Glucocorticoid
Hypersecretion (SAGH)
Subclinical Hypercortisolism (SH)
a mild but autonomous cortisol hypersecretion
from adrenal adenoma detected serendipitously
without any previous suspect of adrenal disease
without signs or symptoms of Cushing's syndrome
(> 5% of all adenomas)
 Distinct from preclinical Cushing’s syndrome (early stage in the
development of patent Cushing’s syndrome).
 Increased prevalence of hypertension, central obesity, diabetes/IGT,
hyperlipoproteinemia; increased cardiovascular risk; reduced BMD.
 High prevalence of disturbed glucose tolerance (61%) in patients with
nonfunctional adrenal incidentaloma (no abnormal low-dose
suppression test).
 Development of postoperative hypocortisolism.
 Benefit of surgery not clear (consider clinical expression and life
expectancy).
Terzolo M et al, Clin Endocrinol 2011
µg/dL
5.0
1.8
Consider presence of MS or
osteoporotic fractures  further
investigation by measurement
of ACTH, UFC, or late-night
salivary cortisol.
Terzolo M et al, Clin Endocrinol 2011
Chiodini I et al, JCEM 2011
INCIDENTALOMA SURRENALICO ED ALTERAZIONI
METABOLICHE
(133 pazienti)
prevalenza delle alterazioni glicemiche
27,41%
43,70%
12,59%
16,30%
Diabetici
IGT
NGT
OGGT non eseguito
Insulina
Recettore
Insulinico
GLUT4
P Tyr
Membrana Plasmatica
Tyr P
PI 3-Chinasi
IRS-1
Tyr P
Glucosio
Subunità
Regolatoria
PI
Subunità
Catalitica
PI 3-P
Docking
Fusione
PDK1
Thr308 P
Akt
“PDK2”
Ser473 P
GLUT4
P Ser
P Ser
Traslocazione GLUT4
Captazione Glucosio
Ser P
AS160 Ser P
GLUT4
Storage
Compartment
Insulina
Recettore
Insulinico
P Tyr
IRS-1
IRS-1
IRS-1
IRS-1
Tyr P
Tyr P
Tyr P
Tyr P
Tyr P
PI 3-Chinasi
PI
Subunità
Subunità
Regolatoria
PI 3-PCatalitica
Subunità PI Subunità
Regolatoria PI Catalitica
3-P
TRASMISSIONE
SEGNALE
Subunità
Regolatoria
Subunità
Regolatoria
Subunità
Regolatoria
Subunità
Regolatoria
Subunità
Catalitica
Insulina
Recettore
Insulinico
P Tyr
IRS-1
IRS-1
IRS-1
IRS-1
Tyr P
PI 3-Chinasi
Tyr P
Subunità
Regolatoria
Tyr P
Subunità PI Subunità
Regolatoria PI Catalitica
3-P
Tyr P
Tyr P
Subunità
Regolatoria
Subunità
Regolatoria
Subunità
Regolatoria
TRASMISSIONE
RIDOTTA
SEGNALE
Subunità
Regolatoria
Subunità
Catalitica
Subunità
Regolatoria
Subunità p85a
Regolatoria
Condizione
Tessuto
Referenza
Eccesso di glucocorticoidi
Muscolo scheletrico
Giorgino F, J. Biol. Chem., 1997
Giorgino F, J. Clin. Invest., 1995
Eccesso di GH
Muscolo scheletrico
Tessuto adiposo
Barbour LA, J. Biol. Chem., 2005
Del Rincon JP, Diabetes, 2007
GH placentare
Muscolo scheletrico
Barbour LA, Endocrinology, 2004
Soggetti insulino-resistenti/DT2 Muscolo scheletrico
Bandyopadhyay GK, Diabetes, 2005
Soggetti dopo carico calorico
Muscolo scheletrico
Cornier M-A, Diabetologia, 2006
Donne post-partum
Muscolo scheletrico
Kirwan J, JCEM, 2004
 Improve the adverse metabolic profile
 Decrease cardiovascular risk
 Reverse some unnoticed symptoms of mild hypercortisolism,
including proximal myopathy, fatigue or cognitive impairment
 Prevent the improbable progression to overt hypercortisolism
with its unquestionable morbidity
Vassiliadi, D. A. & Tsagarakis, S. Nat. Rev. Endocrinol. 7, 668–680 (2011);
Endocrine evaluation
■■Exclude pheochromocytoma: urinary fractionated
metanephrines or plasma free metanephrines
■■Exclude hyperaldosteronism: in patients with hypertension
use aldosterone to renin ratio; if ratio is increased, test further
with saline infusion
■■Exclude autonomous cortisol secretion: cortisol level after
dexamethasone suppression (1 mg overnight or low-dose
dexamethasone suppression test (four times 0.5 mg for 2
days); midnight cortisol (serum or salivary); 24 h urinary free
cortisol; morning ACTH levels; consider measuring DHEAS
levels
Failure to suppress after dexamethasone combined with
another positive test makes the diagnosis probable. Review
possible confounding factors, such as medications or patient
compliance. In case autonomous cortisol secretion is
documented, check for features of the metabolic syndrome (for
example, with OGTT) and osteoporosis.
Indications for surgery (always exclude
pheochromocytoma first)
■■Size >6 cm and/or imaging characteristics suggesting
malignancy
■■Increase in size
■■Functioning tumor
■■Pheochromocytoma: surgery
■■Primary hyperaldosteronism: surgery if unilateral
disease is confirmed
■■Autonomous cortisol secretion: well-established criteria
for surgery are lacking; consider surgery if comorbidities
are present or in cases of clearly abnormal endocrine tests