Author: Milton D Gross
Specialty: Radiology, Nuclear Medicine, Endocrinology
Institution: Division of Nuclear Medicine, Department of Radiology, University of Michigan
City: Ann Arbor; State/Province: Michigan; Postal Code: 48105; Country: United States
Author: Melvyn Korobkin
Specialty: Radiology
Institution: Division of Abdominal Imaging, Department of Radiology, University of Michigan Medical Center
City: Ann Arbor; State/Province: Michigan; Country: United States
Author: Wessam Bou-Assaly
Specialty: Radiology
Institution: Department of Radiology, University of Michigan Medical Center
City: Ann Arbor; State/Province: Michigan; Country: United States
Institution: Radiology Service, Department of Veterans Affairs Health System
City: Ann Arbor; State/Province: Michigan; Country: United States
Author: Domenico Rubello
Specialty: Radiology
Institution: Department of Nuclear Medicine, PET Center, and Medical Physics and Radiology, Santa Maria della Misericordia Hospital
City: Rovigo; Country: Italy
Abstract: Unanticipated adrenal masses are frequently encountered in modern, high resolution diagnostic imaging. Most often, these masses are benign adrenal adenomas, but when detected they necessitate a clinical evaluation sufficient to exclude subclinical endocrine disease, primary adrenal cancer, and remote metastases to the adrenal glands from other malignancies. These "incidentally-discovered" adrenal masses or so-called "adrenal incidentalomas" can be further evaluated with CT, MRI, and nuclear medicine imaging techniques. A substantial literature supports the use of each of these modalities to non-invasively characterize these neoplasms that have been considered by some as a 'disease' by modern imaging technology.
Introduction
Over the last 3 decades the more widespread use of high-resolution CT and MRI have seen the frequent, “incidental” discovery of clinically unsuspected masses of the adrenal glands. Detection of these masses raises the specter of malignancy and forces further diagnostic evaluation to determine their etiology and to distinguish benign masses from those that would substantially change the clinical approach to the patient.
In patients undergoing CT for reasons other than adrenal disease, adrenal masses are incidentally discovered in 0.4-4.5% (Kloos et al., 1995). The majority of adrenal masses, ranging from 7% to 94%, are benign and hormonally non-functional, while in patients with malignancy the incidence of unsuspected adrenal masses ranges from 7% to 68% (Kloos et al., 1995). Metastases from other cancers to the adrenal occur in up to 20% of patients without previously diagnosed cancers and in almost 75 % of patients harboring non-adrenal primary malignancies (Kloos et al., 1995) (Table 1).
The incidence of clinically unsuspected adrenal masses increases with age greater than 30 years, regardless of gender. Clinically silent, hormonally active adrenal masses include tumors that produce hormones from all of the functional zones of the adrenal cortex and the adrenal medulla. As a result it is important that once discovered, and prior to any further imaging, a biochemical evaluation sufficient to exclude pheochromocytoma, normokalemic primary aldosteronism, and subclinical hypercortisolism be done as these conditions are optimally managed by surgical removal of the offending tumor (Young, 2007).
Methods of Adrenal Gland Imaging
Computed tomography is the most common imaging modality that identifies unsuspected adrenal masses in the evaluation of the chest and upper abdomen for diseases unrelated to the adrenal glands (Gross at al., 2005). Both CT and MRI can be used to differentiate normal from abnormal adrenal glands and MRI has been used to characterize incidentally discovered adrenal masses in clinical situations where CT is non-diagnostic (Gross et al., 2009) (Table 2).
Computed tomography and magnetic resonance imaging
Contemporary CT scanners using slice thicknesses of 3-5 mm will reliably depict the adrenal glands in virtually all patients. Comparison of non-contrast to contrast-enhanced CT can be used to distinguish adrenal masses and for evaluating retention and patterns of contrast washout as a means to differentiate adenomas from other adrenal neoplasms (Boland et al., 2008). MRI can be used to advantage in the evaluation of normal adrenal glands and adrenal masses. Gradient-echo, chemical shift MRI with in- and opposed-phrase imaging, and dynamic contrast-enhanced MRI detect lipid content in adrenal adenomas and, when combined with chemical shift ratios, depict the adrenal glands with an efficacy similar to CT (Dunnick et al., 2002). Hybrid scanners marrying CT, and perhaps in the near future MRI, with positron emission tomography (PET) and single photon emission tomography (SPECT) employing radiopharmaceuticals designed to target unique aspects of adrenal gland function(s) offer direct combination of anatomic and functional information that enhances diagnosis and differentiation of benign from malignant adrenal lesions (Gross et al., 2009).
Adrenal scintigraphy
The radiocholesterol analogs, 131I-6β-iodomethyl-19-norcholesterol (NP-59) and selenium-75-6β-iodomethyl-19-norcholesterol (Scintadren®) were some of the first successful radiopharmaceuticals used to image the adrenal cortex (Gross et al., 2007). Radiolabeled inhibitors of enzymes responsible for adrenal steroid hormone biosynthesis like the 11β-hydroxylase inhibitor, carbon-11-metomidate (11C-MTO), can also be used to image neoplasms of adrenocortical origin. Other radiolabeled substrates depict metabolic processes such as the radio-fluorine-labeled 18F-fluorodeoxyglucose (FDG) to identify primary adrenal neoplasms and metastases to the adrenals, while 11C-labeled acetate and 11C- and 18F-labeled choline have been used to depict adrenal adenomas (Gross et al., 2007).
Radiolabeled metaiodobenzylguanidine (MIBG) has been used to identify the adrenal medulla and localize neoplasms of adrenomedullary origin by exploiting norepinephrine-re-uptake mechanisms into the catecholamine storage vesicles of adrenergic tissues.
Hydroxyephedrine, an analog of norepinephrine, can be labeled with 11C or 18F, and is transported into adrenergic nerve terminals by these same mechanisms. The list of catecholamine-based PET radiopharmaceuticals used to image the adrenal medulla, related tissues, and tumors of sympathomedullary origin now includes 11C-epinephrine, 11C- or 18F-hydroxyepinephrine, 18F-fluorodopamine (FDA), and 18F-fluorodihydroxyphenylalanine (18F-DOPA) (Shulkin et al., 2006). Alternatively, somatostatin receptor uptake of specific imaging agents can be used to image tissues that express somatostatin receptors, like the adrenal medulla and many other tissues and neoplasms. Octreotide, a long-acting somatostatin antagonist labeled with a variety of radioisotopes (111Indium, 123Iodine, 99mTechnetium for SPECT, and 68Gallium for PET imaging) can be used to accurately localize and stage primary and metastatic sympathomedullary tumors (Gross et al., 2007).
Imaging Incidentally-discovered Adrenal Masses
The differential diagnostic list of incidentally-discovered adrenal masses is long and a description of all but the most common is outside the scope of this short review. An extensive medical literature is available that describes the imaging characteristics of adrenal masses (Gross et al., 2005).
Adrenal adenoma
Adrenal adenomas are depicted on CT with density values expressed as Hounsfield units (HU) that are similar to normal adrenal tissues and depending upon their lipid content may express HU values similar to tissue water density (Korobkin et al., 1996). Furthermore, adenomas demonstrate increasing density, so-called “enhancement,” after intravenous CT contrast with more rapid loss of contrast — “washout” as compared to adrenal metastases (Korobkin et al., 1998). Like CT, MRI characteristics of adenomas are also similar to normal adrenal tissues. Signal intensity of adenomas is low on T2-weighted MR imaging sequences, but there is overlap (20-30%) with the signal intensity of metastases to the adrenal. Chemical-shift imaging is useful to depict tissue lipid content and is often employed to differentiate adenomas from metastases to the adrenal (Dunnick et al., 2002).
Pheochromocytoma
Pheochromocytomas are often clinically silent and present on high resolution anatomic imaging as incidentally-discovered adrenal masses. These neoplasms show enhancement with intravenous contrast agents in a fashion similar to malignant adrenal masses and occasionally may mimic contrast washout characteristics of benign adrenal adenomas. The imaging uncertainty posed by pheochromocytomas demands a biochemical evaluation sufficient to exclude catecholamine hypersecretion in suspect patients. Concerns over the potential of intravenous contrast-induction of hypertensive crisis have recently been allayed with nonionic contrast agents. Like CT, pheochromocytomas are usually hyperintense on T2-weighted imaging; however, there is overlap and about 30% are hypointense on T2-weighted imaging sequences (Blake et al., 2004).
Adrenal carcinoma
Adrenal carcinoma is a rare neoplasm (~ 2/106 patients) that usually presents late in the course of disease. Adrenal carcinoma is often imaged as a large, heterogeneous abdominal mass with central necrosis, calcification, and tumor venous extension on contrast enhanced CT (Gross et al., 2009). On MRI these neoplasms are hyperintense on both T1- and T2-weighted imaging sequences from intra-tumor hemorrhage and central necrosis.
Adrenal metastases
Adrenal glands are common sites of remote metastases from cancers of the lung, breast, and melanoma. Adrenal metastases can be unilateral, bilateral, and variable in size. CT and MRI are nonspecific. Small metastases are often homogeneous on contrast CT or MRI, while large metastases are heterogeneous as a result of intra-metastasis necrosis and hemorrhage.
Distinguishing benign from malignant adrenal masses
Figure 1. An adrenal mass (arrow) is identified on CT (panel A) with characteristics of an adenoma with a non-contrast CT density (panel B) of 9.8 HU.
CT can be used to distinguish adrenal adenomas from metastases since most adenomas demonstrate non-contrast densities that are lower than metastases to the adrenal. The highest diagnostic efficacy for diagnosis of adrenal adenomas is obtained by selecting a threshold density value of 10 HU on non-contrast CT, as HU values for adenomas and adrenal hyperplasia are typically lower than those of metastases to the adrenal and pheochromocytomas (Figures 1 and 2).
Chemical-shift MRI also differentiates adrenal adenomas from metastases. By exploiting the different resonant frequencies of hydrogen in tissue water and lipid molecules, chemical-shift MRI detects a loss of signal intensity of tissues with high lipid and water content. Using gradient-echo imaging techniques, signal intensity loss on opposed-phase as compared to in-phase images differentiates tissues that contain lipids with high sensitivity and specificity. As lipids are common components of adrenal adenomas that are usually absent in metastases, this difference in lipid content can be exploited for the differentiation of adenomas vs. metastases to the adrenals (Figures 3 and 4).
Figure 2. Abdominal CT of bilateral adrenal masses (arrows) shows persistent enhancement of the right adrenal gland after intravenous contrast at 1.5 (panel B) and 5 min (panel C) after contrast injection in a pattern compatible with metastases to the adrenals.
In a combined histological CT and MRI study of adrenal adenomas there was an inverse relationship between lipid-containing cells and unenhanced CT, and a positive correlation with the relative change in signal intensity on opposed-phase MRI confirming that non-contrast CT and chemical-shift MRI might not necessarily complement each other in the evaluation of adrenal adenomas (Outwater et al., 1996). Contrast-enhanced CT images of the adrenals are obtained about 1 minute after a bolus intravenous injection of contrast and at this time point the attenuation values of adenomas and metastases are nearly identical (Figure 2B and Figure 5C). However, over time adenomas demonstrate loss of contrast enhancement and attenuation values on contrast enhanced CT of < 30-40 HU at 10-15 minutes post contrast injection can be used to distinguish, with few exceptions, adenomas from other adrenal masses (Gross el al., 2009).
Figure 3. MRI of a right adrenal nodule (arrows) demonstrates post-contrast enhancement on T1-weighted imaging (panel C) and displays loss of signal on out-of-phase (panel B) compared to in-phase imaging (panel A) confirming the mass as an adrenal adenoma.
Adrenal gland contrast washout as a percentage of initial enhancement is another parameter that can be used to identify adenomas from other adrenal masses. Adrenal adenomas have characteristic washout percentages of ~ 60% at 15 minutes post contrast administration corresponding to a sensitivity of 88% and a specificity of 96% for diagnosis of adenoma (Korobkin et al., 1998) (Figure 5). Further, so-called “lipid-poor” adenomas with unenhanced CT attenuation of >10 HU have contrast enhancement washout values that are nearly identical to those of lipid-rich adenomas confirming the value of differential washout as a means to identify adrenal adenomas from other adrenal masses (Caoili et al., 2000).
Distinguishing adrenal adenoma from carcinoma
Figure 4. MRI of a right adrenal mass demonstrates heterogeneous post-contrast enhancement (panel C) with no signal loss on out-of-phase imaging (panel B) vs. in-phase imaging (panel A) confirming the mass to be an adrenal metastasis.
Any adrenal mass larger than 5 to 6 cm in diameter is considered suspicious for an adrenocortical carcinoma. Large, non-secreting pheochromocytomas, adrenal carcinoma, or adrenal metastases may be indistinguishable by CT and MRI. Size criteria for resection of adrenal masses varies widely from 3.5 to 6 cm, and while there is controversy concerning the approach to smaller masses there is general agreement that masses > 6 cm, regardless of their imaging characteristics, should be removed.
Scintigraphy of adrenal masses
There are a host of scintigraphic imaging agents, with each targeting a unique characteristic of adrenal gland function that can be used to assess the etiology of incidentally-discovered adrenal masses. Adrenal adenomas can be depicted with iodocholesterol with positive and negative predictive values of 89% and 100%, respectively, and the lateralization of tracer uptake to one gland may be predictive of the development of future functional autonomy.
Metaiodbenzylguanidine images masses of adrenomedulla origin with positive and negative predictive values of 83% and 100%, respectively, while 18F-FDG separated benign from malignant adrenal lesions with 100% sensitivity and specificity (Maurea et al., 2001). As a result, if functional imaging is to be used to evaluate adrenal masses in patients with no history of cancer, radiocholesterol scintigraphy should be the first imaging procedure to identify the most common incidentally-discovered adrenal mass, a benign adrenal adenoma, followed by MIBG to identify clinically silent pheochromocytomas. Should MIBG be non-diagnostic, 18F-FDG is to be used to identify a potentially malignant adrenal mass or remote metastasis to the adrenal. Conversely, in patients with a prior history of cancer, 18F-FDG would be the most optimal first imaging study in the search for metastatic disease to the adrenal followed in sequence by iodocholesterol and MIBG.
Figure 5. A left adrenal gland mass (arrow) with a density of 1.5 HU on non-contrast CT (panels A and B) increases after intravenous contrast administration to 50 HU on early post-contrast enhanced images (panel C), and falls to 4 HU on the delayed images (panel D). The calculated washout of 95% is compatible with a lipid rich, adrenal adenoma.
18F-FDG-PET can differentiate benign from malignant adrenal lesions and metastases to the adrenal (Figure 6). In a study of 150 patients with adrenal masses, 18F-FDG-PET had a sensitivity of 98.5% and a specificity of 92% at a standardized uptake value (SUV) threshold of 3.1 and with the addition of CT to FDG-PET specificity increased to 98% with all masses correctly characterized as benign or malignant (Metser et al., 2006). While in 50 patients with known or suspected malignancy, 18F-FDG-PET had a sensitivity of 100%, a specificity of 94%, and an accuracy of 96%, and by using the liver as a ‘normal’ comparison tissue it improved the sensitivity of 18F-FDG for detecting malignant adrenal lesions without sacrificing sensitivity (Yun et al., 2001). More recently 18F-FDG-PET was shown in a prospective multicenter trial to accurately differentiate adrenocortical adenomas from adrenal carcinomas and in particular a subgroup of masses with indeterminate findings on CT (Groussain et al., 2009).
In comparative studies of the 11β-hydroxylase inhibitor, 11C-MTO, and 18F-FDG in incidentally-discovered masses, 11C-MTO identified lesions of adrenocortical origin with the highest SUV in adrenocortical carcinoma, followed by hypersecretory adrenal cortical adenomas and non-hypersecretory adenomas, although 11C-MTO-PET did not distinguish benign adrenocortical neoplasms from adrenocortical carcinoma (Hennings et al., 2006). 18F-FDG can be also used to image pheochromocytomas and adrenocortical carcinoma and to differentiate these neoplasms from other non-hypersecreting and most hypersecreting adrenal adenomas.
Figure 6. PET/CT scans of adrenal masses (white arrows). An 18F-FDG scan (panel A) shows no appreciable tracer accumulation in a left adrenal mass seen on CT (panel B) compatible with an adrenal adenoma. An adrenal metastasis from lung cancer (black arrows) is depicted on an 18F-FDG scan (panel C) as an intense focus of tracer uptake in a small left adrenal mass on CT (panel D).
Pheochromocytomas can be reliably imaged with 123I- or 131I-MIBG with PET/CT using 18F-dopamine or 18F-DOPA (Shulkin et al., 2006) (Figure 7). In a comparison of the efficacy of 18F-FDA, 123I-MIBG, and 111In-octreotide, 18F-FDA demonstrated the highest sensitivity in the localization of intra-adrenal and metastatic pheochromocytomas, followed by 123I-MIBG and 111In-octreotide for intra-adrenal pheochromocytoma, while the efficacy of 18F-FDA and 123I-MIBG were equivalent (Ilias et al., 2008). If catecholamine analogs are not successful in imaging, the neoplasm may have experienced malignant dedifferentiation, and 18F-FDG or 111In-octreotide can be used to localize metastases and guide subsequent therapy.
Summary
Incidentally-discovered adrenal masses are commonly encountered in modern high-resolution imaging. The list of differential diagnostic possibilities of incidentally-discovered adrenal masses is large, but fortunately, most are benign and non-hyperfunctioning adenomas. The first consideration in the evaluation of an incidentally-discovered adrenal mass is its functional status and should include a biochemical evaluation sufficient to exclude clinically-silent endocrine disease. CT, MRI, and scintigraphy can be used to characterize incidentally-discovered adrenal masses and distinguish adrenal adenomas from metastases to the adrenals and other adrenal neoplasms. An understanding of the imaging techniques used to distinguish benign from malignant and other incidentally-discovered adrenal masses speeds diagnosis, optimizes therapy, and decreases costs in the evaluation of these neoplasms.
Figure 7. A small, left adrenal mass (arrow) on CT (panel A) demonstrates intense 18F-DOPA uptake (panel B) in a patient with hypertension and a prior negative 123I-MIBG scan who was later shown to have elevated catecholamines compatible with a pheochromocytoma.
References
Blake MA. Kalra MK. Maher MM. Sahani DV. Sweeney AT. Mueller PR. Hahn PF. Boland GW. Pheochromocytoma: an imaging chameleon. Radiographics 24(Suppl 1):S87-99, 2004.
Boland GW. Blake MA. Hahn PF. Mayo-Smith WW. Incidental adrenal lesions: principles, techniques, and algorithms for imaging characterization. Radiology 249(3):756-75, 2008.
Caoili EM. Korobkin M. Francis IR. Cohan RH. Dunnick NR. Delayed enhanced CT of lipid-poor adrenal adenomas. Am J Roentgenol 175(5):1411-5, 2000.
Dunnick NR and Korobkin M. Imaging of adrenal incidentalomas: current status. Am J Roentgenol 179(3):559-68, 2002.
Gross MD, Korobkin M, Hussain H, Cho KJ, Bui C. “Adrenal Gland Imaging” Chapter 126. Endocrinology, 5th Edition. JL. Jameson and LJ. Degroot, Eds. W.B. Saunders, Philadelphia, USA, pp. 2425-2453, 2005.
Gross MD, Avram A, Fig LM, Rubello D. Contemporary adrenal scintigraphy. European J Nucl Med Mol Imaging 34:547-57, 2007.
Gross MD, Korobkin M, Bou Assaly W, Dwamena B, Djekidel M. Contemporary imaging of incidentally discovered adrenal masses. Nat Rev Urol 6:363-73, 2009.
Groussin L, Bonardel G, Silvera S, Tissier F, Coste J, Abiven G, Libe R, Bienvenu M, Alberini JL, Salenave S, Bouchard P, et al. 18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J Clin Endocrinol Metab 94(5):1713-22, 2009.
Hennings J, Lindhe O, Bergstrom M, Langstrom B, Sundin A, Hellman P. [11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings. J Clin Endocrinol Metab 91(4):1410-4, 2006.
Ilias I, Chen CC, Carrasquillo JA, Whatley M, Ling A, Lazurova I, Adams KT, Perera S, Pacak K. Comparison of 6-18F-fluorodopamine PET with 123I metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med 49(10):1613-9, 2008.
Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal masses. Endocr Rev 16(4):460-84, 1995.
Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F. CT time-attenuation washout curves of adrenal adenomas and nonadenomas. Am J Roentgenol 170(3):747-52, 1998.
Korobkin M, Giordano TJ, Brodeur FJ, Francis IR, Siegelman ES, Quint LE, Dunnick NR, Heiken JP, Wang HH. Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 200(3):743-7, 1996.
Maurea S, Klain M, Mainolfi C, Ziviello M, Salvatore M. The diagnostic role of radionuclide imaging in evaluation of patients with nonhypersecreting adrenal masses. J Nucl Med 42(6):884-92, 2001.
Metser U, Miller E, Lerman H, Lievshitz G, Avital S, Even-Sapir E. 18F-FDG PET/CT in the evaluation of adrenal masses. J Nucl Med 47(1):32-7, 2006.
Outwater EK, Siegelman ES, Huang AB, Birnbaum BA. Adrenal masses: correlation between CT attenuation value and chemical shift ratio at MR imaging with in-phase and opposed-phase sequences. Radiology 200(3):749-52, 1996.
Shulkin BL, Ilias I, Sisson JC, Pacak K. Current trends in functional imaging of pheochromocytomas and paragangliomas. Ann N Y Acad Sci 1073:374-82, 2006.
Yun M, Kim W, Alnafisi N, Lacorte L, Jang S, Alavi A. 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med 42(12):1795-9, 2001.
[Discovery Medicine, Volume 9, Number 44, January 2010. Pre-published.]
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From
http://www.discoverymedicine.com/Milton-D-Gross/2010/01/04/incidentally-discovered-adrenal-masses/
, Andrea Patrizi1, Chiara Romiti1, Giorgio Arnaldi2 and Marco Boscaro2
