Differential diagnosis of ACTH-dependent hypercortisolism:imaging versus laboratory

Massimiliano Andrioli Æ Francesca Pecori Giraldi ÆMartina De Martin Æ Agnese Cattaneo ÆChiara Carzaniga Æ Francesco Cavagnini

Published online: 18 March 2009

� Springer Science+Business Media, LLC 2009

Abstract Differential diagnosis of ACTH-dependent

Cushing’s syndrome often presents major difficulties.

Diagnostic troubles are increased by suboptimal specificity

of endocrine tests, the rarity of ectopic ACTH secretion

and the frequent incidental discovery of pituitary adeno-

mas. A 43-year-old female reported with mild signs and

symptoms of hypercortisolism, and initial hormonal tests

and results of pituitary imaging (7-mm adenoma) were

suggestive for Cushing’s disease. However, inadequate

response to corticotrophin-releasing hormone and failure to

suppress after 8 mg dexamethasone pointed towards an

ectopic source. Total body CT scan visualized only a small,

non-specific nodule in the right posterior costophrenic

excavation. Inferior petrosal sinus sampling revealed an

absent center:periphery ACTH gradient but octreoscan and18F-FDG-PET-CT failed to detect abnormal tracer accu-

mulation. We weighed results of the laboratory with those

of imaging and decided to remove the lung nodule.

Pathology identified a typical, ACTH-staining carcinoid and

the diagnosis was confirmed by postsurgical hypoadrenal-

ism. In conclusion, imaging may prove unsatisfactory or

even misleading for the etiologial diagnosis of ACTH-

dependent Cushing’s syndrome and should therefore be

interpreted only in context with results of hormonal dynamic

testing.

Keywords Cushing � Pituitary adenoma �Ectopic ACTH secretion � Carcinoid

Introduction

Ectopic ACTH secretion, although a rare occurrence,

always has to be excluded when dealing with ACTH-

dependent Cushing’s syndrome and suboptimal specificity

of hormonal and imaging procedures often makes this dis-

tinction difficult. Marked Cushingoid features, e.g., severe

hypertension, hypokalemia, hyperpigmentation, had been

considered highly suggestive of ectopic ACTH secretion in

the past but the experience accrued in recent years revealed

that mild hypercortisolism is not so rare among patients

with ectopic ACTH secretion. Diagnostic problems are also

increased by the frequent incidental discovery of incidental

pituitary masses [1] and by the difficulties in visualizing

small neuroendocrine tumors.

We herein describe a case of an ACTH-dependent

Cushing’s syndrome in which imaging was not discrimi-

natory and, even, misleading and the correct diagnosis was

established essentially through laboratory testing.

Clinical case

A 43-year-old woman with signs and symptoms of mild

hypercortisolism (i.e., modest weight gain, hypertension,

hypertrichosis, secondary amenorrhea, hypokalemia, mood

changes) was evaluated for Cushing’s syndrome. Initial

investigations were suggestive for Cushing’s disease (urinary

free cortisol 1,147–2,088–2,440 nmol/24 h, normal \220;

serum cortisol after 1 mg dexamethasone 744 nmol/l, normal

\50 nmol/l; plasma ACTH 33 pmol/l, normal \10 pmol/l

and 7-mm left paramedian pituitary adenoma at MRI; Fig. 1a)

and transsphenoidal adenomectomy had been advised.

Our reassessment confirmed ACTH-dependent hyper-

cortisolism and revealed a borderline cortisol response to

M. Andrioli � F. Pecori Giraldi � M. De Martin � A. Cattaneo �C. Carzaniga � F. Cavagnini (&)

Chair of Endocrinology, Ospedale San Luca IRCCS, Istituto

Auxologico Italiano, University of Milan, Via Spagnoletto 3,

20149 Milan, Italy

e-mail: cavagnini@auxologico.it

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Pituitary (2009) 12:294–296

DOI 10.1007/s11102-009-0174-2

CRH (ACTH: from 35 to 41 pmol/l, increase by 18%;

cortisol from 938 to 1,131 nmol/l, increase by 23%) and

failure of cortisol to suppress after 8 mg dexamethasone

(from 882 to 800 nmol/l, decrease by 10%). These findings

challenged the diagnosis of Cushing’s disease and favored

an extrapituitary ACTH source. Total body CT scan visu-

alized only a small (8 9 11 mm), contrast-enhanced, non-

specific intraparenchymal lung nodule in the right posterior

costophrenic excavation (Fig. 1b). Inferior petrosal sinus

sampling (IPSS) was performed and revealed an absent

center:periphery ACTH gradient (basal 1.3 and after

CRH 1.6), thus upholding an extrapituitary ACTH

source. However, 111Indio-octreotide Octreoscan and even

18F-fluorodeoxyglucose PET-CT failed to detect any

abnormal tracer accumulation. The results of the diagnostic

work-up were therefore discordant, with laboratory inves-

tigations pointing towards ectopic ACTH secretion and

imaging studies favoring Cushing’s disease. Summarizing,

our patient presented mildly symptomatic ACTH-depen-

dent Cushing’s syndrome, a pituitary microadenoma,

hormonal testing and IPSS suggesting an extrapituitary

ACTH source and a non-specific lung lesion which failed

to label with either octreotide or glucose. On balance, we

reasoned that (a) hormonal testing should carry more

weight than imaging in the differential diagnosis of

Cushing’s syndrome, and (b) missing a neuroendocrine

tumor could be more dangerous than failure to immediately

remove a pituitary ACTH-secreting microadenoma. Thus,

we referred the patient to a lung surgeon for thoracic

exploration and right inferior lung lobectomy was per-

formed. Pathology of the nodule revealed an ACTH-

staining typical carcinoid and the diagnosis of ectopic

ACTH secretion was confirmed by immediate postsurgical

hypoadrenalism. Features of Cushing’s syndrome disap-

peared and follow-up imaging of the pituitary adenoma at

3 years was superimposable.

Discussion

This case is paradigmatic for the ongoing problems with

imaging in ACTH-dependent Cushing’s syndrome. As

Cushing’s disease is far more frequent than ectopic ACTH

secretion, pituitary imaging has been recommended during

the initial diagnostic work-up [2] and, in fact, imaging

revealed a pituitary microadenoma in our patient thus

strengthening the a priori most likely diagnosis, i.e.,

Cushing’s disease. At this point, the patient was referred to

the neurosurgeon and only a more accurate endocrine

evaluation spared her unnecessary pituitary surgery.

The diagnostic accuracy of tests used for the differential

diagnosis of ACTH-dependent Cushing’s syndrome is not

absolute and there is no uniformly accepted flowchart for

the distinction between pituitary and ectopic ACTH

secretion but, rather, recommendations based upon each

center’s experience. Even IPSS does not achieve absolute

sensitivity as patients with Cushing’s disease may present

false negative results [3, 4]. Pituitary-dependent hyper-

cortisolism can therefore not be completely ruled out after

negative test responses although, in our patient, concordant

negative responses to at all three diagnostic procedures

(CRH stimulation, dexamethasone suppression test and

IPSS) argued against Cushing’s disease.

On the other hand, 10% of the general population is

known to present incidental pituitary microadenomas [1]

Fig. 1 Pituitary MRI showing a 7-mm left paramedian adenoma and

slight ipsilateral stalk deviation (a). Chest CT. Arrow indicates a

small (8 9 11 mm), contrast-enhanced, apparently non-specific nod-

ule in the right posterior costophrenic excavation (b)

Pituitary (2009) 12:294–296 295

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and incidental pituitary findings can therefore be expected

also among patients with ectopic ACTH secretion. Indeed,

coexistence of incidental pituitary tumors with ACTH-

secreting extrapituitary tumors, although rare, has been

observed both in large series and isolated case reports.

Most lesions were small (\5 mm), low signal areas

deemed inconclusive or ‘‘possible pituitary microade-

noma’’ [2, 4, 5] whereas an indisputable microadenoma

was detected in the present case. Pituitary macroadenoma

and ectopic ACTH secretion coincided in one patient but

Cushing’s syndrome developed some years after the non-

secreting pituitary macroadenoma had been removed, thus

imaging did not cloud the diagnostic work-up [6]. It fol-

lows that pituitary imaging should be used to substantiate

hormonal tests indicative of pituitary ACTH source and not

as an aid to the etiological diagnosis.

In our patient, the ectopic neuroendocrine ACTH-

secreting tumor itself proved difficult to visualize as its

appearance at CT scan was considered non-specific and

negative results of both octreoscan and PET-CT cast seri-

ous doubts as to its functionality. It is known, however, that

sensitivity of these procedures for ectopic ACTH secretion

is far from absolute and negative scans do not rule out

small neuroendocrine tumors [7, 8].

In conclusion, imaging may prove unsatisfactory or even

misleading in the evaluation of ACTH-dependent Cush-

ing’s syndrome, as in our patient, and should therefore be

interpreted only in context with results of hormonal

dynamic testing. Diagnosis of ectopic ACTH secretion

requires exhaustive diagnostic procedures and a certain

degree of clinical experience and boldness.

References

1. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH

(1994) Pituitary magnetic resonance imaging in normal human

volunteers: occult adenomas in the general population. Ann Int

Med 120:917–920

2. Friedman TC, Zuckerbraun E, Lee ML, Kabil MS, Shahinian H

(2007) Dynamic pituitary MRI has high sensitivity and specificity

for the diagnosis of mild Cushing’s syndrome and should be part of

the initial workup. Horm Metab Res 39:451–456. doi:10.1055/

s-2007-980192

3. Swearingen B, Katznelson L, Miller K, Grinspoon S, Waltman A,

Dorer DJ, Klibanski A, Biller BM (2004) Diagnostic errors after

inferior petrosal sinus sampling. J Clin Endocrinol Metab

89:3752–3763. doi:10.1210/jc.2003-032249

4. Invitti C, Pecori Giraldi F, De Martin M, Cavagnini F, The Study

Group of the Italian Society of Endocrinology on the Pathophys-

iology of the Hypothalamic-Pituitary-Adrenal Axis (1999)

Diagnosis and management of Cushing’s syndrome: results of an

Italian multicentre study. J Clin Endocrinol Metab 84:440–448.

doi:10.1210/jc.84.2.440

5. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK

(2005) Cushing’s syndrome due to ectopic corticotropin secretion:

twenty years’ experience at the National Institutes of Health. J Clin

Endocrinol Metab 90:4955–4962. doi:10.1210/jc.2004-2527

6. Wong M, Isa SH, Kamaruddin NA, Khalid BA (2007) ACTH

producing pulmonary carcinoid and pituitary macroadenoma: a

fortuitous association? Med J Malaysia 62:168–170

7. Kumar J, Spring M, Carroll PV, Barrington SF, Powrie JK (2006)

18Flurodeoxyglucose positron emission tomography in the local-

ization of ectopic ACTH-secreting neuroendocrine tumours. Clin

Endocrinol (Oxf) 64:371–374

8. Pacak K, Ilias I, Chen CC, Carrasquillo JA, Whatley M, Nieman

LK (2004) The role of [(18)] Flurodeoxyglucose positron emission

tomography and [(111)In]-diethylenetriaminepentaacetate-D-Phe-

pentetreotide scintigraphy in the localization of ectopic adrenocor-

ticotropin-secreting tumours causing Cushing’s syndrome. J Clin

Endocrinol Metab 89:2214–2221. doi:10.1210/jc.2003-031812

296 Pituitary (2009) 12:294–296

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