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ENDOCRINE SURGERY
also removal of invaded adjacent organs. In the
French study, 23% underwent a unilateral subcostal incision, 23% bilateral subcostal incisions, 22% thoracoabdominal incision, and
22% midline incisions [9]. In this series, surgery
was curative (R0) in 71% of the cases, lymphadenectomy was performed in 33% of cases. En
bloc resection beyond the adrenal was necessary
in 42% of cases: kidney (29%), spleen (10%), VC
thrombus (6%), liver resections (7%), and left
pancreatectomy (4%).
Recurrence
Recurrences may occur long after initial treatment [1]; however, most recurrences and/or
metastasis are diagnosed within 5 years of initial
surgery. This observation may have important
implications for patient information and followup; it may also provide a rationale for the duration of adjuvant therapy after curative surgery.
Unfortunately, the first recurrence is likely
followed by other relapses, and the disease-free
period is progressively shortened with upcoming recurrences being characterized by increasingly aggressive tumor behavior.
Adjuvant Therapy
Radiotherapy as an adjuvant treatment after
surgery has been poorly studied, and although
previously not recommended, a recent study
demonstrated reduced local recurrence compared with matched controls [13].
Assessing the effectiveness of most published
adjuvant treatment protocols for ACC has been
difficult, since most series have been limited by
the inclusion of relatively few subjects, with
tumors at various stages.
Even in patients with apparently localized disease (stages I & II) and adequate surgery, metastases will very often develop within 6–24 months.
Mitotane
Mitotane ( o,p0-DDD), is the only adrenal-specific
agent available for the treatment of ACC. Mitotane
exerts a specific cytotoxic effect on adrenocortical
cells producing focal degeneration of the fascicular
and particularly the reticular zone, whereas
changes of the glomerulosa are relatively slight.
Metabolic activation is essential for its adrenolytic
activity.
Developing cancer cells will vary in their ability to metabolize Mitotane because of alterations
in the metabolic process. Tumors with an ability
to metabolize Mitotane respond, but those that
are unable to metabolize the drug may not.
Mitotane treatment induces adrenal insufficiency and requires glucocorticoid replacement.
Mitotane has a narrow therapeutic window. Several publications have established the impact of
monitoring blood Mitotane concentration for
predicting efficacy and toxicity (14 mg/l), as
adverse effects occur frequently and are more
often dose limiting. More than 80% of all
patients experience at least one undesirable
effect. Those are mainly gastrointestinal, or
involve the central nervous system, leading in
numerous cases to interruption of the treatment, also due to the lack of proven efficacy.
The dilemma facing the physician when there
is no evidence of residual disease is whether to
follow patients without initiating treatment or
to use adjuvant therapy in the form of radiation,
Mitotane, or systemic chemotherapy.
Numerous studies have shown that Mitotane
fails to improve overall survival [9, 15], and that
only 20–25% of patients respond in terms of
tumor growth [12, 11]. Although the control of
hormone excess exists in the majority of
patients, a complete response in patients with
advanced ACC is extremely rare, and survival
advantage of Mitotane was apparently only proven in stage IV disease [9].
Given the toxic effects that are associated with
what had been regarded as therapeutic doses and
the lack of evidence for a real beneficial effect in
previous studies, the use of Mitotane as adjuvant
therapy for ACC has not been widely used.
Recently, a credible study from Terzolo et al.
[3] came to the conclusion that patients receiving Mitotane after radical surgery had a recurrence-free survival that was two to three times
as long as that of those not receiving the drug.
Overall survival was increased in this group of
patients. The study provides a compelling and
very interesting rationale for the use of Mitotane
as effective adjuvant therapy, even at low doses
(1–3 g/day) (see Fig. 30.2).
Experience with cytotoxic chemotherapy in
ACC is still limited, several combinations of
agents have been used, and available evidence
suggest that cisplatin alone or in combination
411
ADRENOCORTICAL CARCINOMA
Fig. 30.2. Kaplan–Meier estimates of recurrence-free survival and overall survival. Reprinted with permission from Terzolo M,
Angeli A, Fassnacht M et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372–2380.
Copyright # 2007 Massachusetts Medical Society. All rights reserved.
Table 30.2. Therapeutic strategy for ACC by stage and/or clinical situation
Stage I-III
412
ENDOCRINE SURGERY
RO Adjuvant treatment Follow up /3mth
Recurrence Surgery (tumor+met) Complete resection
Or
Stage IV
R Non 0 Mitotane/chemo
Mitotane- radiotherapy
FIRM-ACT Progression
with etoposide has some activity in ACC. Only a
minority of patients seem to respond to most of
the protocols. An Italian protocol combine
Mitotane, etoposide, doxorubicine, and cisplatin [35] with a response close to 50%, a less toxic
protocol combining mitotane and streptozotocin has also been developed. A first phase III
trial in ACC comparing those two regimens is
currently ongoing (FIRM-ACT).
Hypersecretion of hormonal steroid can also
be treated with other adrenostatic drugs such as
ketoconazole or etomidate.
Future Prospects
After decades of limited progress, it seems that
some progress in the treatment of ACC is taking
place; however, current treatments remain disappointing and better therapies are needed.
Hope could come from therapeutic monoclonal antibodies, tyrosine kinase inhibitors, or
immunotherapy, but true progress will only follow a better understanding of the molecular
pathogenesis of ACC, and a better knowledge
about tumor response to drugs that could
Incomplete
Not possible
Surgery + treat
Regression/stable
Switch chemo
greatly influence quality of life and prognosis
of patients with ACC.
Conclusion
ACC is a rare neoplasm with a poor prognosis.
Young patients present with signs of steroid
hormone excess or an abdominal mass. Often,
at initial diagnosis, metastases are already present, making the disease frustrating and disappointing to deal with for physicians and
surgeons.
Complete tumor removal (R0 resection)
offers the best chance for long-term survival,
and therefore surgery is the treatment of
choice in stages I–III ACC. Currently laparoscopic surgery is not recommended for proven ACC.
Despite tumor resection for cure, patients
will very often develop local recurrence and
distant metastases; thus adjuvant treatment
options need tobe considered. Nowadays, Mitotane is the best adjuvant treatment and according to recent data, is indicated for all patients
(see Table 30.2).
413
ADRENOCORTICAL CARCINOMA
References
1. Abiven G, Coste J, Groussin L, Anract P, Tissier F,
Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical
and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in
a serie of 202 consecutives patients. J Clin Endocrinol
Metab. 2006;91(7):2650–2655.
2. Kebebew E, Reiff E, Duh QY et al. Extent of disease at
presentation and outcome for adrenocortical carcinoma:
have we made progress? World J Surg. 2006;30:872–878.
3. Terzolo M, Angeli A, Fassnacht M et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J
Med. 2007;356:2372–2380.
4. Cofield KR, III, Cantley LK, Geisinger KR et al. Adrenocortical carcinoma arising from a long-standing adrenal
mass. Mayo Clin Proc. 2005;80:264–266.
5. Kirschner LS. Emerging treatment strategies for adrenocortical carcinoma: a new hope. J Clin Endocrinol
Metab. 2006;91:14–21.
6. Sidhu S, Gicquel C, Bambach CP et al. Clinical and
molecular aspects of adrenocortical tumourigenesis.
ANZ J Surg. 2003;73:727–738.
7. Logie A,Boulle N, GastonV etal. Autocrine role of IGF-II
in proliferation of human adrenocortical carcinoma NCI
H295R cell line. J Mol Endocrinol. 1999;23:23–32.
8. Reincke M, Beuschlein F, Slawik M et al. Molecular
adrenocortical tumourigenesis. Eur J Clin Invest.
2000;30(Suppl 3):63–68.
9. Icard P, Goudet P, Charpenay C et al. Adrenocortical
carcinomas: surgical trends and results of a 253-patient
series from the French Association of Endocrine Surgeons study group. World J Surg. 2001;25:891–897.
10. Tauchmanova L, Colao A, Marzano LA et al. Andrenocortical carcinomas: twelve-year prospective experience. World J Surg. 2004;28:896–903.
11. Proye C, Armstrong J, Pattou F. Adrenocortical Carcinoma: Nonfunctioning and Functioning. In: Clark OH,
Duh QY, Kebebew E editors. Textbook of Endocrine
Surgery. Philadelphia: ElsevierSaunders; 2005. 604–611.
12. Allolio B, Fassnacht M. Clinical review: Adrenocortical
carcinoma: clinical update. J Clin Endocrinol Metab.
2006;91:2027–2037.
13. Fassnacht M, Hahner S, Polat B et al. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence
of adrenocortical carcinoma. J Clin Endocrinol Metab.
2006;91:4501–4504.
14. Kaye T, CrapoL. The Cushing’s syndrome: anupdate on
diagnostic tests. Ann Intern Med. 1990;112:434–444.
15. van Heerden JA, Grant C, WeaverA. Primary carcinoma
of the adrenal cortex: an institutional surgical perspective. Acta Chir Aust. 1993;25:216.
16. MacFarlane D.Cancer ofthe Adrenal cortex:The natural
history, prognosis, and treatment in a study of 55 cases.
Ann R Coll Surg. 13958;23:155.
17.PeixJL.Incidentalome.In:ChapuisY,PeixJLeditors.
Chirurgie des GlandesSurrenales.Paris:Arnette;1994.115.
18. Boland G, Lee M, Gazelle G, Halpern E, McNicholas M,
Mueller P. Characterization of adrenal masses using
unenhanced CT: an analysis of the CT literature. Am J
Roentgenol. 1998;171:201–204.
19. Remer EM, Motta-Ramirez GA, Shepardson LB et al. CT
histogram analysis in pathologically proven adrenal
masses. AJR Am J Roentgenol. 2006;187:191–196.
20. Szolar DH, Korobkin M, Reittner P et al. Adrenocortical
carcinomas and adrenal pheochromocytomas: mass and
enhancement loss evaluation at delayed contrastenhanced CT. Radiology. 2005;234:479–485.
21. Korobkin M, Lombardi TJ, Aisen A, rancis I, Quint E,
Dunnick N, Londy F, Shapiro B, Gross M, Thompson N.
Characterization of adrenal masses with chemical shift
and gadolinium-enhanced MR imaging. Radiology.
1995;197:411–418.
22. Jana S, Zhang T, Milstein D, Isasi C, Blaufaox M. FDGPET and CT characterisationof adrenal lesionsin cancer
patients. Eur J Nucl Med Mol Imaging. 2006;33:29–35.
23. Aubert S, Wacrenier A, Leroy X. Weiss system revisited:
a clinicopthological and immunohistochemical study of
49 adrenocortical timors. Am J Surg Path. 2002;26:1612.
24. Luton JP, Cerdas S, Billaud L et al. Clinical features of
adrenocortical carcinoma, prognostic factors, and the effect
of mitotane therapy. N Engl J Med. 1990;322:1195–1201.
25. Bellantone R, Ferrante A, et al. Role of reoperation in
recurrence of ACC: results from 188 cases collected in
the Italian National registry for Adrenal Tumor Surgery.
1997; 122:1212–1218.
26. Schteingart DE, Doherty G, Gauger PG, Giordano TJ,
Hammer GD, Korobkin M, Worden FP. Management
of patients with adrenal cancer: reccomendation of an
International consensus conference. Endocr Related
Cancer. 2005;12:667–680.
27. Smith C, Weber C, Amerson J. Laparoscopic Adrenalectomy: new gold standard. World J Surg.
1999;23:389–396.
28. Henry JF, Sebag F, Iacobone M et al. Results of laparoscopic adrenalectomy for large and potentially malignant tumors. World J Surg. 2002;26:1043–1047.
29. Saunders B, DohertyG. Laparoscopicadrenalectomy for
malignant disease. Lancet Oncol. 2004;5:718–726.
30. Shen WT, Lim RC, Siperstein AE et al. Laparoscopic vs
open adrenalectomy for the treatment ofprimary hyperaldosteronism. Arch Surg. 1999;134:628–631.
31. Cobb WS, Kercher KW, Sing RF et al. Laparoscopic
adrenalectomy for malignancy. Am J Surg.
2005;189:405–411.
32. Gonzales R, Shapiro S, Sarlis N, Vassilopoulo-Sellin R,
Perrier ND, Evans DLJ. Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery.
2005;138:1078–1085.
33. Hamoir E, Meurisse M, Defechereux T. Is laparoscopic
resection of a malignant corticoadrenaloma feasible?
Case report of early, diffuse and massive peritoneal
recurrence after attempted laparoscopic resection. Ann
Chir. 1998;52(364):368.
34. Palazzo FF, Sebag F, Sierra M et al. Long-term outcome following laparoscopic adrenalectomy for large
solid adrenal cortex tumors. World J Surg.
2006;30:893–898.
35. Berruti A, Terzolo M, Sperone P et al. Etoposide,
doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large
prospective phase II trial. Endocr Relat Cancer.
2005;12:657–666.
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31
Incidentaloma
Dimitrios A. Linos
Introduction
Historically the adrenal tumor discovered
incidentally, usually during an imaging procedure (CT, MRI, ultrasound) for symptoms unrelated to adrenal disease (e.g., back pain), is
called an incidentaloma [1]. As more physicians
order these easily available imaging studies for
common diseases potentially related to adrenal
pathology (and not the known syndromes),
such as mild and nonparoxysmal hypertension,
diffuse obesity, and diabetes, an increasing
number of unsuspected (but hardly incidental)
adrenal tumors are found. These tumors should
be included with the true incidentalomas under
the broader term ‘‘adrenaloma’’ because they
share the same diagnostic and therapeutic
dilemmas [2]. The term ‘‘adrenaloma’’ implies
that the discovered tumor (incidentally or not)
arises from the adrenal but is not obviously
an aldosteronoma, a Cushing’s syndrome adenoma, a pheochromocytoma, a virilizing or
feminizing tumor, or a functioning adrenal
carcinoma.
Recently at a State of the Science Conference
at the National Institute of Health Conference,
the term ‘‘Clinically Inapparent Adrenal Mass’’
was coined [3]. The widespread teaching is that
most incidentalomas are indolent tumors, nonfunctioning, and asymptomatic, causing no
harm to the patient [4, 5]. Recent studies, however, have shown that a high percentage of these
tumors can be subclinically functioning, and
cause symptoms milder than those encountered
in the well-knownadrenal hyperfunctioning syndromes but are still potentially harmful to the
patient [6–14, 20, 33, 42, 46]. Thus, the suggested
screening tests including serum potassium, urinary vanillylmandelicacid (VMA), and serum cortisol are not sufficient, and a more detailed and
in-depth laboratory investigation is necessary.
The fear of adrenal carcinoma that dictated the
approach to these tumors in the past (with the
main emphasis on the size of the tumor) should
be changed to the fear of the subtle function of
these usually benign adrenal cortical adenomas
with coexistent metabolic pathology (e.g., hypertension, obesity, diabetes).
Frequency
The overall frequency of adrenal adenomas in
87,065 autopsies in 25 studies was 5.9% (range
1.1–32%) [15]. The frequency of adrenal masses
discovered by CT, MRI, or ultrasonography is
somewhat lower. Abecassis et al. [16] in a 2-year
period examined 1,459 patients and found 63
(4.3%) with adrenal masses. Of those, 19 patients
(1.3% of examined patients and 30% of patients
with adrenal masses) had adrenalomas. At the
Mayo Clinic [17], in a 5-year period with 61,054
patients undergoing CT scanning, an adrenal
abnormality was found in 2,066 (3.4%) patients;
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_31, Ó Springer-Verlag London Limited 2009
415
416
ENDOCRINE SURGERY
among these, 259 patients (12.5%) had an adrenaloma or adrenal lesion larger than 1 cm,
without biochemical evidence or symptoms
suggestive of cortical or medullary hypersecretion or general constitutional symptoms suggestive of malignant disease. Similar findings
have been described in more recent studies
[18–20]. Thus, in the era of widespread use of
high-resolution ultrasonography, new generation CT scans and MRI, a 5% incidence of adrenalomas is anticipated.
Pathology
The majority of surgically removedincidentalomas
have been classified as nonfunctioning cortical
adenomas [21–23]. Benign masses such as nodular
hyperplasia, adrenal cysts, myelolipomas, ganglioneuromas, hematomas, hamartomas, hemangiomas, leiomyomas, neurofibromas, teratomas, as
well as infections (tuberculosis, fungal, echinococcosis, nocardiosis) are also included in the pathology of these resected tumors. Potentially lethal
neoplasms, however, such as pheochromocytomas
and primary carcinomas are always first on the
list of resected adrenalomas [24–28, 46]. Pheochromocytoma is the most frequently found hormoneproducing adrenaloma that occasionally has a
normal preoperative laboratory evaluation
[29–34]. Few cases of aldosteronomas and androgen-producing adenomas have been described
among cases of surgically removed adrenalomas
[3–35]. In a large multicenter, retrospective Italian
study of 380 surgically treated adrenalomas
(out of 1,096 collected), 198 (52%) were cortical
adenomas, 47 (12%) were cortical carcinomas, 42
(11%) were pheochromocytomas, and 93 (25%)
were other less-frequent tumors [6]. Approximately 5% of incidentalomas are adrenocortical
carcinomas.
The Goal of Evaluation
Although adrenal incidentalomas appear
‘‘non-functioning’’ by definition, more investigators have shown that a high percentage of
them may be subclinically functioning and/or
associated with other metabolic abnormalities
based on clinical and essential laboratory findings (Fig. 31.1). In a multicenter, retrospective
evaluation of 1,096 patients with adrenal incidentaloma, the work-up revealed that 9.2%
had subclinical Cushing’s syndrome, 4.2%
had pheochromocytoma, and 1.6% had clinically unsuspected aldosteronomas [22].
Rossi et al. [10] prospectively followed 50
consecutive patients with incidentalomas.
Detailed hormonal investigation found 12 of 50
(24%) to have subclinical Cushing’s syndrome
defined as an abnormal response to at least two
standard tests of the hypothalamus–pituitary–
adrenal axis function, in the absence of clinical
signs of Cushing’s syndrome. In the same study,
92% of patients had hypertension, 50% obesity,
42% type 2 diabetes mellitus, and 50% abnormal
serum lipid concentrations. The clinical and
hormonal features improved in all patients treated by adrenalectomy but were unchanged in
those who did not undergo surgery (follow-up
9–73 months).
Interestingly, all 13 patients who had resection of truly nonfunctioning adenomas because
of large size had improved clinically to such an
extent that antihypertensive and antidiabetic
therapy was reduced or discontinued. All the
improvements persisted during follow-up.
Another multicenter study [12] of 64 consecutive patients with adrenal incidentalomas
found a higher than expected prevalence of
abnormal glucose tolerance in 39 (61%) patients.
The same authors [36] following 62 consecutive
patients with adrenal incidentalomas found
abnormal glucose tolerance curves in 66%.
Midorikawa et al. [11] studying 15 patients
with incidentalomas (4 with subclinical Cushing
and 11 with truly nonfunctioning tumors)
found a high prevalence of altered glucose tolerance and insulin resistance. Adrenalectomy
reversed insulin resistance in all patients with
subclinical functioning and truly nonfunctioning adrenal adenomas.
Terzolo et al. [8] followed 41 patients with
incidentalomas (12 with subclinical Cushing’s
syndrome) and compared them with 41 controls. He found that the 2-h post-challenge glucose was significantly higher in these patients
than in controls. Similarly, both systolic and
diastolic blood pressures were higher in studied
patients. The calculated whole-body insulin
sensitivity index (derived from the oral glucose
tolerance test) was significantly reduced in the
patients. They concluded that patients with
these tumors (subclinically functioning or
417
INCIDENTALOMA
Fig. 31.1. Adrenal incidentalomas with ‘‘unexpected’’ clinical behavior. (a) Cortical adenoma on a 37-year-old female with
subclinical Cushing’s syndrome and metabolic syndrome significantly improved after surgery. (b) Cortical adenoma on a 40-year-old
male that during a 3-year follow-up turned from ‘‘nonfunctioning’’ to overt Cushing’s syndrome. (c) Aldosteronoma on a 45-year-old
hypertensive but normokalemic male followed for years for this 2.5 cm ‘‘incidental’’ mass. (d) Pheochromocytoma on a 32-yearold asymptomatic normotensive female. (e) ‘‘Indolent’’ myelolipoma that ruptured during its follow up causing severe intraablominal bleeding on a 27-year-old male. (f)Solitary metastatic adrenal carcinoma, 10 years after hysterectomy for cervical cancer
on a 62-year-old female. (Reprinted with permission from Linos DA, Adrenal glands: diagnostic aspects and surgical therapy.
Heidelberg: Springer-Verlag; 2005. 243).
nonfunctioning) display some features of the
metabolic syndrome such as impaired glucose
tolerance, increased blood pressure, and high
triglyceride levels.
Garrapa et al. [13] evaluated body composition and fat distribution, as measured by dualenergy X-ray absorptiometry (DEXA) in women
with nonfunctioning adrenal incidentalomas
and in women with Cushing’s syndrome compared with healthy controls matched for age,
menopausal status, and body mass index
(BMI). Women with adrenal incidentalomas
had larger waist circumference reflecting
intraabdominal fat. The blood pressure was
higher in patients with these tumors than in
controls, and 50% of patients were hypertensive.
418
ENDOCRINE SURGERY
High-density lipoprotein cholesterol levels and
mean triglyceride values were also higher in
patients with adrenal incidentalomas than in
controls. If central fat deposition, hypertension,
and low HDL are important risk factors for cardiovascular disease, then patients with adrenal
incidentalomas, whether subclinically functioning or nonfunctioning, are at higher risk than the
general population for cardiovascular disease.
Chiodin et al. [14] performed a longitudinal
study evaluating the rate of spinal and femoral
bone loss levels in 24 women with adrenal incidentalomas. They were divided into two groups
on the basis of the median value of urinary
cortisol excretion. The group with higher cortisol values (subclinical Cushing levels) had more
lumbar trabecular bone loss than those with low
cortisol secretion (not hypersecreting tumors).
Therefore the cavalier attitude toward adrenal incidentalomas should be changed. These
tumors are in between the normal and the
pathological stage. They should be screened to
rule out (1) subclinical Cushing’s syndrome, (2)
subclinical pheochromocytoma, (3) subclinical
primary aldosteronism, and (4) adrenal carcinoma (primary or solitary metastasis).
Screening for Subclinical
Cushing’s Syndrome
confirmatory high-dose dexamethasone suppression test (8 mg), a corticotropin-releasing
hormone (CRH) test, analysis of diurnal cortisol
rhythm and growth hormone (GH) response to
GHRH [8]. If serum cortisol concentrations are
not suppressible by high-dose dexamethasone,
the diagnosis of subclinical Cushing’s syndrome
is established. As already discussed, glucose
tolerance is altered in patients with adrenal
incidentalomas (with and without subclinical
Cushing), and a glucose tolerance test is recommended in patients with adrenal incidentalomas
[10, 12, 39]. Finally, bone mineral density of the
spine should be performed to detect reduced
bone mass in patients with subclinical Cushing’s syndrome [14].
Adrenal scintigraphy with
norcholesterol (NP 59) can reveal a ‘‘functioning’’
but not ‘‘hypersecretory’’ tumor when there is an
uptake of the nucleotide in the tumor site and nouptake inthe contralateral suppressed gland. Some
authors [40, 41] showed a significant positive correlation between abnormal cortical secretion and
NP 59 uptake, while others [15] considered NP 59
scanning not cost-effective because it requires several days to obtain the images. In addition, routine
use of NP-59 scan is not recommended because of
the inability of adrenal gland with hemorrhage or
inflammation to take up NP-59.
131
I-6b-iodomethyl-
Patients with subclinical Cushing’s syndrome
have none of the signs and symptoms of typical
Cushing’s syndrome (plethora, moon face, central obesity, easy bruising, proximal muscle
weakness, acne, osteoporosis, etc.). The frequency of subclinical Cushing’s syndrome
among patients with adrenaloma ranges from
12 to 24% [10, 37]. Depending on the amount of
glucocorticoids secreted, the clinical significance of subclinical Cushing’s syndrome ranges
from slightly attenuated diurnal cortisol rhythm
to atrophy of the contralateral adrenal gland, a
dangerous condition after unilateral adrenalectomy if appropriate perioperative therapeutic
measures are not taken early enough [38].
The best screening test for autonomous cortisol secretion is the short dexamethasone suppression test. A suppressed serum cortisol
(<2 mg/dl or 50 nmol/l) excludes Cushing’s syndrome. A serum cortisol greater than 2 mg/dl
requires further investigation, including a
Screening for ‘‘Subclinical
Pheochromocytoma’’
The typical patient with pheochromocytoma is
hypertensive and may have paroxysmal hypertension and related symptoms (headache, hypertensive crisis, sweating, and cardiac arrhythmias).
The proposed term ‘‘subclinical pheochromocytoma’’ refers to the totally asymptomatic adrenal
incidentaloma that histologically proves to be a
pheochromocytoma. In several series of adrenal
incidentalomas, the frequency of pheochromocytomas ranges from 10 to 40% [31, 34]. Although
thepercentageofasymptomaticpheochromocytomas among patients with nonfunctioning
adrenal tumors is relatively high, hormonal evaluation, which is a measurement of 24-h urinary
metanephrines and VMA or fractionated urinary
catecholamines, is commonly diagnostic. In the
National Italian Study Group, 27 patients (3.4% of
419
INCIDENTALOMA
the total patients with incidentaloma) were found
to have pheochromocytoma; 24-h urinary catecholamine and VMA concentrations were elevated in 86 and 4.6% of patients, respectively
[22], indicating that a combination of tests is
more useful clinically than an individual test.
The efficacy of single-voided (‘‘spot’’) urine metanephrine and normetanephrine assays for diagnosing pheochromocytoma has recently been
documented. Such tests may avoid the inconvenience of 24-h urinary collection [42].
Ten of 42 patients (24%) with adrenal incidentalomahad borderline evaluationsin urine or
plasma metanephrine levels,three of whomhad a
pheochromocytoma (30%) in a recent study [42].
Interestingly, in these 10 patients no clinical factors such as hypertension, symptomatology, or
size allowed differentiation between those with
and without pheochromocytomas. Preoperatively, it is wise to prepare this group of patients
(with incidentaloma and borderline metanephrine levels) with alpha blockade knowing that only
a percentage of them will eventually have histologically proven pheochromocytoma. On the
other hand, there is no indication for routine
131
use of
scintigraphy in the evaluation of an adrenaloma
unless catecholamine and urinary metabolites
are elevated.
I-meta-iodobenzylguanidine (I-MIBG)
Screening for ‘‘Subclinical
Primary Aldosteronism’’
Typical primary aldosteronism is characterized
by hypertension with hypokalemia, elevation of
plasma aldosterone, and suppressed plasma
renin activity (PRA). Subclinical primary aldosteronism describes the patient with adrenaloma
who is normotensive or hypertensive with normokalemia [43]. More than 40% of patients with
primary aldosteronism are normokalemic;
therefore, the previously recommended measurement of potassium as the only test to rule
out primary aldosteronism in the case of adrenal
incidentalomas should be abandoned [43].
Instead, a detailed time-consuming evaluation is
necessary, especially in all hypertensive patients,
to rule out primary aldosteronism, which may be
the cause of hypertension in up to 15% of these
patients [44, 45]. In a normotensive patient with a
serum potassium level greater than 3.9 nmol/l, no
further hormonal evaluation is necessary. The
screening for subclinical primary aldosteronism
should include, in addition to serum potassium,
the upright aldosterone level to PRA ratio, since a
single value of aldosterone may be normal.
Patients with two or more samples of positive
aldosterone/PRA ratio (>40) should undergo the
fluorocortisone suppression test (0.4 mg every
day for 4 days) or the acute saline-suppression
test (2 l of 0.9% NaCl solution infused intravenously in 4 h) to confirm the diagnosis. Bilateral
adrenal venous sampling with measurements of
aldosterone and cortisol levels is the necessary
next step to lateralize and to determine the
subtype of primary aldosteronsim in order to
identify the patient who will be cured through
surgical treatment.
Screening for Adrenal
Carcinoma
The risk of an adrenal incidentaloma harboring
a primary carcinoma of the adrenal varies from 4
to 25% depending on the size of the tumor [46,
58]. The annual incidence of the latter has been
estimated to range from 1 case per 600,000 to
1 case per 1.6 million persons. Its prevalence is
approximately 0.0012% [47]. In contrast, metastatic carcinoma to the adrenal is a common
finding in patients with lung, breast, colon, and
other extra-adrenal malignancies. In published
series of surgically resected adrenalomas, the frequency of histologically confirmed primary adrenal carcinoma ranges from 4.2 to 25% [6]. The
frequency of adrenal metastasis from lung cancer
at autopsy ranges from 17 to 38%. In patients with
an adrenal mass in the setting of extra-adrenal
malignancy, the probability of this mass being
metastatic ranges from 32 to 73% [5, 34, 48].
Size of Tumor
The size of an adrenal incidentaloma is frequently used to predict potential malignancy
and the need for surgery. Although most clinically treated adrenal malignancies are discovered when they are larger than 6 cm in diameter,
several reports have described very large
tumors that never metastasized and small