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doi:10.1515/enr-2017-0005
Radiology of the adrenal incidentalomas. Review of the literature
FARRUGIA FA, MARTIKOS G, SURGEON C, TZANETIS P, MISIAKOS E, ZAVRAS N, CHARALAMPOPOULOS A
Third Department of Surgery, University of Athens, ATTIKON Hospital, Athens, Greece E-mail: farrugiafa@gmail.com
The term “adrenal incidentaloma” is a radiological term. Adrenal incidentalomas are adrenal tumors discovered in an imaging study that has been obtained for indications exclusive to adrenal conditions (Udelsman 2001; Linos 2003; Bulow et al. 2006; Anagnostis et al. 2009). This definition excludes patients undergoing imaging testing as part of staging and work-up for cancer (Grum- bach et al. 2003; Anagnostis et al. 2009). Papierska et al. (2013) have added the prerequisite that the size of a tumor must be “greater than 1cm in diameter”, in order to be called incidentaloma. Although in the most cases these masses are non-hypersecreting and benign, they still represent an important clinical concern because of the risk of malignancy or hormone hyperfunction (Barzon et al. 2003). The adrenal tumors belong to the commonest incidental findings having been discov- ered (Kanagarajah et al. 2012).
Key words: adrenal incidentaloma, radiology, ultrasound, computer tomography, magnatic resonance, functional imaging
The adrenal incidentaloma (AI) is a term that may be applied to various diseases sharing the same way of (incidental) radiological discovery. Because of the great heterogeneity, it has been called a modern tech- nology disease (Chidiac and Aron 1997), which is ac- tually a cluster of diseases (Angeli and Terzolo 2002).
A large study on AI has been conducted in Italy by Mantero et al. (2000). The aim of their study was to perform a national survey on AI. They have retained for the final analysis, 1004 cases, from which 380 pa- tients were operated (38%). The majority of the oper- ated cases were 52% adenomas, 12% adrenomal car- cinoma (ACC), 11% pheochromocytomas, 5% cystic lesions, 4% ganglioneuromas, 2% metastases and 6% other histological diagnoses (Mantero et al. 2000).
In the above-mentioned survey, it has been re- ported that the reasons for an abdominal imaging procedure were (non) “aspecific” symptoms (36%); abdominal pain (36%), including either an ill-defined discomfort or biliary and renal colic; postsurgery fol- low-up (8%); acute abdomen (1.5%); abdominal trau-
ma (1.5%); and other (17%). No significant difference in the gender indications was apparent (Mantero et al. 2000).
The adrenal masses have been detected by abdomi- nal ultrasound in 631 cases (71%), computer tomog- raphy (CT) in 247 (28%), and magnetic resonance imaging (MRI) in 9 (1%) (Mantero et al. 2000). In addition, this study has shown that abdominal U/S detected more often right-sided than left-sided tu- mors (65% vs. 26%), whereas CT detected them at similar rates (43% vs. 43%). They have concluded that abdominal U/S might be able to visualize the right adrenal gland better than the left one (Mantero et al. 2000).
Despite the fact that this study was done in the year 2000, somebody may think that it is outdated and may be misleading in this era of high resolution cross sectional imagining by CT and MRI. It is the largest study of this kind in the literature and it is still cited in almost all the studies regarding the AI. Besides, not all the hospitals around the world have
the most recent imaging modalities. This study is the only study that describes the full epidemiologi- cal characteristics of the presentation of the AI. The majority of the studies after 2000 are restricted to the incidence of AI in CT or MRI or both (Blake et al. 2010; Boland et al. 2008; Jain 2013; Kim et al. 2013; Herr et al. 2014; Paterson et al. 2014).
The fact that ultrasound have been more frequently used, may be surprising, but the same has been found in the recent studies of Paprieska et al. (2013) and Ta- buchi et al. (2015).
Location: In recent studies, AI was more frequent- ly localized on the left than the right side (Cho et al. 2013; Kim et al. 2013; Tabuchi et al. 2015). Bilateral masses have been observed from 9.4-20% (Kasper- lik-Zaluska et al. 2010; Tabuchi et al. 2015). Bilateral incidentalomas are more likely associated with sub- clinical Cushing syndrome and less likely with the pheochromocytoma (Pasternak et al. 2015). The aver- age diameter of tumors was 21±11mm (Paterson et al. 2014; Tabuchi et al. 2015).
Material and Methods
We conducted an internet search using the refer- ence software “ENDNOTE version 7” (2003) and connected by the help of the “connect” command with “Pub-Med” and used the search terms “Adre- nal” and “Incidentaloma”, and “Radiology” and “Im- aging” without any time limit. We gathered 662 stud- ies, the oldest with the term “Adrenal Incidentaloma” was from 1982. From the literature, we kept only the studies of AI that were relevant with the radiology of AI. The aim of the study was to present the radiologi- cal characteristics of AI, having in mind the surgeons rather than the radiologists.
Prevalence. Improvements in abdominal imaging techniques and technologies have resulted in the de- tection of an increasing number of AIs (NIH 2002).
The prevalence of adrenal incidentalomas varies in the different autopic studies, depending on the age of the patient and the size of the tumor. The mean prev- alence in a total of 71206 cases from the literature is 2.3%, ranging from 1 to 8.7%, without significant differences between females and males (Barzon et al. 2003). These masses are associated with changes tak- ing place in the organ in the course of a physiological process of aging (Dobbie 1969; Hornsby 2002). The prevalence of AI varies with age. The prevalence of AI detected in autopsy is less than 1% for ages younger than 30 years and increases to 7% in those having 70 years of age or older (Barzon et al. 2003; Zeiger et al. 2011; Papierska et al. 2013).
Causes of adrenal mases (Conder et al. 2009).
A. Functional: Adenoma causing Conn’s or Cushing’s syndrome; Pheochromocytoma; Aldosteronoma; Adrenal carcinoma;
B. Malignant: Metastases; Carcinoma; Lympho- ma; Neuroblastoma;
C. Benign: Non-functioning adenoma; Angio- myolipoma; Cysts; Hemorrhage.
Radiology of adrenal diseases:
An introduction about adrenal radiology. Ad- renal lesions can be categorized as primary or meta- static, benign or malignant, and functioning or non- functioning ones (Young 2007; Boland et al. 2008). The primary goal of imaging is to distinguish among adrenal adenoma, adrenal carcinoma, pheochromo- cytoma, and metastatic lesions (Zeiger et al. 2009).
The strength and practicality of any imaging test devised to differentiate these lesions will ultimately depend on the test sensitivity and specificity (Boland et al. 2008). First, the test needs to be sufficiently sen- sitive to detect focal adrenal lesions when present. However, while high sensitivity is useful, the critical characteristic of an imaging test is its ability to char- acterize the adrenal lesions, i.e. to distinguish those that require further evaluation from those that can be safely left alone (Boland et al. 2008). High-test speci- ficity is, therefore the crux of adrenal imaging, and tests must be devised that are as close to 100% specific as possible (Boland et al. 1998).
Despite the fact that adrenals can be a site of me- tastasis from other organs, there are, unfortunately, no recommendations about concurrent radiological studies in other organs, which may be the site of a primary cancer likely to metastise in adrenals - like for example, lungs (Chest X Ray) in the work-up of AI in all the studies that we had studied.
Ultrasound (U/S). As it has been reported in an Italian study (Mantero et al. 2000), 71% of AI are first discovered by the ultrasonography. This has been also reiterated by other studies mentioned above. The nor- mal adrenal gland that is 3-6mm thick and adrenal masses as small as 1.3 cm can be delineated (Yeh 1980).
Although the frequency of visualizing normal adrenal glands (78.5% on the right and 44% on the left) with sonography is not as high as with CT scan, masses are more readily detected than the normal glands (Yeh 1980). Their physiological thickness does not exceed 12mm, while the sensitivity of this meth- od is over 90% for diagnosing tumors 2 cm in size (Trojan et al. 2002).
When a suprarenal mass is demonstrated by ul- trasound, it is necessary to establish whether it is of an adrenal or renal origin. If between the kidney and
the mass a margin can be demonstrated, the origin is most likely adrenal. In masses of renal origin, a mar- gin should not be evident. Delineation of this margin can be readily accomplished by gray scale technique. It is somewhat more difficult to accomplish this with bistable scans (Forsythe et al. 1977).
Before the development of modern cross-sectional imaging techniques, tumors were characterized based on their vascularity as shown by angiography (Ghia- tas et al. 1996). Neoplastic vessels give high frequency signals due to high velocity flow resulting from their low resistance, due to lack of smooth muscle in the wall of the vessels and the arteriovenous anastomoses (Taylor et al. 1988).
Ghiatas et al. (1996) have studied 47 patients to find out whether it is possible to use “the flow imag- ing in the differential diagnosis of adrenal masses”. They have concluded that “Doppler ultrasound and power imaging do not help in the differentiation of benign from malignant adrenal masses” (Ghiatas et al. 1996). Among tumors, often lymphoma and endo- crine tumors (pheochromocytoma) are hypervascu- larized (Nurnberg et al. 2011).
Contrast enhanced ultrasound gave promising re- sults in a few studies (Slonina et al. 2006; Friedrich- Rust et al. 2008; Nurnberg et al. 2011).
Another modality of ultrasound is CEUS (Contrast enhanced ultrasound). Lipoma and myelolipoma regularly do not show a wash out effect. Malignant tumors do not show a characteristic phenomenon, both wash out and late contrast accumulation occurs. The contrast media performance is inhomogeneous, e.g. also adenomas show a wash out phenomenon.
Ultrasound elastography and Endoscopic ultra- sound (EUS) with SSWE (supersonic shear wave elastography) are new promising techniques for the evaluation of the adrenal masses (Saftoiu and Vilma 2006; Stapa et al. 2014). Endoscopic ultrasound (EUS) with SSWE is a feasible technique that can be applied during ultrasound of the abdomen and retroperito- neum and it is a promising method for the evaluation of left adrenal gland masses and presents potential for the differentiation of solid and cystic adrenal le- sions (Saftoiu and Vilma 2006; Stapa et al. 2014). As a general rule, malignant masses tend to be harder (blue). No consistent elastography criteria have been proposed so far (Popescu and Saftoiu 2014).
Today, even after numerous studies, it is impossible to distinguish exactly between the benign (adenoma) and malignant tumors (metastasis) without histology or cytology (Nurnberg et al. 2011).
Computer tomography (CT). The AIs are detect- ed by CT scan at about 28% (Mantero et al. 2000). CT
is the primary diagnostic imaging modality for the evaluation of the adrenal disorders (Karstaedt et al. 1978; Montagne et al. 1978; Wilms et al. 1979; Abrams et al. 1982). On the pre-contrast CT, the adrenals have a soft tissue density similar to that of the liver (Lee 1998). The adrenal cortex and medulla cannot be reli- ably distinguished by either CT or MRI (Karstaedt et al. 1978; Montagne et al. 1978). Although, no strict measurements have been standardized, any area thicker than 10 mm is probably abnormal (Lee 1998). It must be recognized that in the face of stress (as may be seen in severely ill patients), the adrenals may become enlarged in response to physiologically high circulating adrenocorticotropic hormone (ACTH) levels (Boland et al. 2008).
When optimal CT scanning technique is used, normal or pathologic adrenal glands can be well vi- sualized in virtually in 100% of patients (Lee 1998). Large and small masses and hyperplasia can be read- ily detected when present (Lee 1998). With proper technique, masses smaller than 5 mm can be detected (Korobkin et al. 1979; Eghrari et al. 1980; Abrams et al. 1982). The accuracy of CT for diagnosis of adrenal masses has been reported as being better than 90% (Lee 1998) and a normal appearance of the adrenal effectively excludes the presence of an adrenal tumor (Lee 1998). Because many small adrenal masses are isodence with adrenal tissue, they are detected as fo- cal bulges on the otherwise smooth adrenal surface. Focal enlargement is a more important finding than any measurement (NIH 2002).
According to the NIH Statement (2002), the size and appearance of an adrenal mass on CT or MRI may help distinguish between benign and malignant lesions. The available data suggest that nearly all le- sions smaller than 4 cm are benign. They use the words “may” and “suggest”, meaning that we are not 100% sure from CT and MRI about the nature of the tumor neither from its size, nor from its appearance. One has to keep in mind that all the adrenocortical carcinomas (ACC) before they become more that 4 cm they were 0.5, 1, 1.5, 2, 3, 3.5 cm.
The evaluation of radiation attenuation coefficient, i.e. the so-called density, is the most important ele- ment of CT scan description of an adrenal tumor. Density is expressed in Hounsfield Units (HU) and represents the value of X-radiation attenuation lin- ear coefficient for the examined tissue in comparison with the coefficient measured for water. The range is 2000 HU: the coefficient for water is 0 HU, for air (-) 1000 HU, for adipose tissue about (-) 100 HU and for soft tissues (+) 20 - (+) 70 HU (Papierska et al. 2013).
During diagnostic workup for AI, the density
should be assessed before and 1 min after the ad- ministration of i.v. contrast enhancement, followed by acquisition (washout phase) 10 or 15 min later. The so-called imaging phenotype of a tumor, which can be “mild” or “suspicious”, can be assessed on the grounds of measurements recorded in this protocol. A tumor with a mild imaging phenotype is one with low density, i.e. ≤10 HU. This low density means that the lipid fraction of the tumor is high, which is char- acteristic of lipid-rich mild adenoma (NIH 2002). In principle, an initial density ≥10 HU may not require further density assessment following contrast agent administration (Papierska et al. 2013). According to the NIH Statement (2002), “an homogeneous mass with a low attenuation value (less than 10 HU) on CT scan is likely a benign adenoma”, this is also con- firmed and by other authors (Mansmann et al. 2004; Stajgis et al. 2005; Ilias et al. 2007; Pantalone et al. 2010; Zeiger et al. 2011; Papierska et al. 2013).
The calculation of so-called contrast washout co- efficients expressed in percentage, is based on the density differences. An absolute coefficient is a quo- tient in which the difference between maximal den- sity (during the 1st min) and the density after 10 or 15 min, is the numerator; while the difference between the maximal value and the initial value is the de- nominator (result is multiplied by 100%) (Dunnick and Korobkin 2002; Papierska et al. 2013). This pa- rameter is used for examinations performed accord- ing to the adrenal protocol with initially planned subsequent duration of exposure (Papierska et al. 2013).
Upon the discovery of an adrenal tumor during the vascular phase on thorax CT scan without ini- tial density value, the relative coefficient can be used. It represents the proportion between the decrease in the density from the 1st min until the 10th min of the examination and the density during the 1st min. An absolute washout coefficient that is greater than 50% after 10 min, 60% after 15 min and a relative washout coefficient that is greater than 40% indicates a mild character of the lesion. This allows the diagnosis of a lipid-poor adenoma, i.e. a lesion that requires sur- gery only in case of the confirmed hormonal activity (ACTH-independent hypercortisolemia or primary hyperaldosteronism) (Mansmann et al. 2004; Ilias et al. 2007; Zeiger et al. 2011; Papierska et al. 2013).
Perhaps the most useful principle that can aid characterization of AI is evaluation of any relevant prior imaging test results. As a rule of thumb, any adrenal lesion that increases in size on serial images (usually obtained 6 months apart) can be considered malignant (Goldman et al. 1996; van Niel et al. 1999).
Caveats to this statement include some benign lesions (adenomas and myelolipomas) that, in rare cases, can increase in size very slightly over this time period. Furthermore, hemorrhage into the adrenal gland, whether traumatic or spontaneous (as in my- elolipomas) will cause abrupt adrenal enlargement (Boland et al. 2008).
In addition to the above, substantial minority of pheochromocytomas have absolute or relative wash- out characteristics that overlap with those of lipid- poor adenomas (Patel et al. 2013), this was confirmed and by Blake et al. (2003), who have concluded that pheochromocytoma should be included in the dif- ferential diagnosis of nodules meeting washout or at- tenuation criteria for adrenal adenoma.
In practice, however, any increase in size is gen- erally considered malignant until proved otherwise (Boland et al. 2008). Conversely, stability of a lesion signifies benignity (Mayo-Smith et al. 2001; Dun- nick and Korobkin 2002). It is highly unusual for un- treated malignant lesions to demonstrate stability on 6-month follow-up images (Young Jr 2007). Accord- ing to the NIH Statement (2002), “in patients with tumors that remain stable on two imaging studies carried out at least 6 months apart and do not exhibit hormonal hypersecretion over 4 years, further follow up may not be warranted.
Furthermore, larger lesions are much more likely to be malignant (Mansmann et al. 2004; Young Jr 2007). Once an AI is larger than 4cm, the chance that it is malignant increases to approximately 70% (85% if larger than 6 cm) (Dunnick and Korobkin 2002). Some authors have placed these percentages much lower, but it is unusual in clinical practice to see be- nign lesions larger than 4 cm (Szolar et al. 2005). For lesions larger than 4-5 cm, ACC should be strongly considered, particularly if the patient has no other history of malignancy (Rozenblit et al. 1996; Mayo- Smith et al. 2001; Dunnick and Korobkin 2002).
Both benign and malignant lesions can be hetero- geneous in attenuation, particularly after the admin- istration of intravenous contrast medium (Boland et al. 2008). Large necrotic areas in the lesion usually signify malignancy. Conversely, metastases, when detected, are often homogeneous and similar in ap- pearance to adenomas, especially when small (Cho et al. 2013).
Song et al. (2013) have conducted a study to deter- mine whether morphologic features of adrenal mass- es detected at initial contrast-enhanced MDCT can differentiate benign from malignant disease. They concluded that when an adrenal mass has malignant morphologic features, such as an irregular margin
and heterogeneous density with a thick enhancing rim at presenting contrast-enhanced MDCT, it likely represents a malignant lesion. The remaining mor- phologic features, including a smooth margin and homogeneous density, being seen in both the benign and malignant disease, are not sufficient for charac- terization of the adrenal masses particularly in pa- tients with a known history of malignancy.
In a Korean Study, female gender and non-contrast Hounsfield units value of >10 were significant risk factors for functional adrenal tumors (Mantero et al. 2000).
Magnetic resonance imaging. Of all the AI, 1% is discovered by MRI (Mantero et al. 2000). The adre- nals can be delineated in nearly all the patients with MRI (Schteingart et al. 2005). Sensitivity, specificity, positive predictive value and negative predictive val- ue for CT and MRI range from 90% to almost 100% according to various studies (Lee 1998; Anagnostis et al. 2009; Boland 2011; Sundin 2012; Herr et al. 2014).
The normal adrenal is of low to intermediate sig- nal on T1- and T2-weighted imaging (Blake 2010). An MRI evaluation of the adrenals should usually con- sist of both T1 and T2 images (Krestin et al. 1989; Lee 1998). Dynamic serial T1W images obtained after intravenous administration of Gd-DTPA are used to show enhancement patterns of adrenal masses (Pa- pierska et al. 2013).
Techniques sensitive to the presence of lipid (such as phase contrast, Dixon method, STIR (short inver- sion time inversion recovery sequence), and radio- frequency-selective fat suppression are most helpful in differentiating between subacute hemorrhage and fat-containing adrenal masses, both of which can ap- pear as high signal lesions on T1-weighted spin echo images (Lee 1998).
STIR sequence is based on T1 differences of the protons. Fat has a shorter T1 value than water (Unal et al. 2015). STIR is primarily used to reveal fluid, not fat. Short T1, which corresponds to short T1W and T2W imaging, enhances tissues that have more fluid content (i.e. tumors). However, signal from protons that have short T1 similar to fat, such as subacute hemorrhage, gadolinium, and viscous fluid, are also adversely suppressed (Bley et al. 2010; Pokharel et al. 2013; Unal et al. 2015).
STIR is an inversion-recovery MR imaging se- quence that uses a 1800 RF pulse followed by a 900 pulse and another 1800 pulse (to produce an echo). In “traditional” inversion recovery, the time between the first 1800 pulse and the 900 pulse (termed T1) is relatively long (300-500 ms), so that T1-weighting is produced. In STIR, the T1 time is made relatively
short (100-170) in order to produce fat suppression. To accomplish fat suppression, one must select the T1 value such that the 900 pulse occurs exactly when the longitudinal magnetization of fat spins is at zero, while, at the same time, some longitudinal magneti- zation is still present in water spins. This effectively produces both suppression (blackening) of signal from fat tissue and relative enhancement of signal from water-containing tissues. STIR also enhances differences between the water content of various tis- sues, because it is T1-plus T2-weighted, an additive effect that might potentially highlight disease (Paling et al. 1988; Shuman et al. 1989).
The principle of Dixon technique depends on in- phase and opposed-phase imaging (Unal et al. 2015). The Dixon technique acquires two separate images with a modified spin echo pulse sequence. One is a conventional spin echo image with water and fat signals in-phase and the other is acquired with the readout gradient slightly shifted so that the water and fat signals are 180° out-of-phase. Dixon showed that from these two images, a water-only image and a fat- only image could be generated. The water only image by the Dixon’s technique can serve the purpose of fat suppression, an important and widely used imaging option for clinical MRI. Additionally, the availabil- ity of both the water-only and fat-only images allows direct image based water and fat quantitation (Ma 2008).
Diffusion-Weighted MRI (DWI) is a technique used to detect the state of molecular translational mo- tion of water in the tissue. In some tumors, densely packed malignant cells, causes restricted diffusion of water relative to that of normal tissue. DWI is quanti- fied by the apparent diffusion coefficient map-appar- ent diffusion coefficient (ADC). Since ADC reflects primarily diffusion coefficient of extra-cellular water, ADC values tend to be lower for tumors compared to normal tissue. Contrary to cancer, in benign lesions, extra-cellular space volume is higher, thus ADC val- ues are higher as well. For this reason, DWI is an important complementary tool in the evaluation of pathologic conditions in the abdomen and is increas- ingly used in routine imaging (Miller et al. 2010).
Miller et al. (2010) have conducted a study which aim was to evaluate the utility of ADC values for characterizing adrenal lesions and determine if DWI can distinguish lipid-rich from lipid-poor adeno- mas. They have concluded that unlike lesion size and percentage decrease in SI, the ADCs were not useful in distinguishing benign from malignant adrenal lesions. Lipid-poor adenomas could not be distin- guished from lipid-rich adenomas and all other non-
fatty lesions of the adrenal gland with DWI (Miller et al. 2010).
Fortunately, radiological characterization of an AI can be done with high sensitivity and specificity us- ing well-established techniques such, CT attenuation without contrast enhancement, washout CT tech- nique and chemical-shift MR imaging. Thus, further evaluation with diffusion-weighted MRI is not essen- tial (Miller et al. 2010).
FDG-PET and adrenal scintigraphy. Data for FDG-PET and adrenal scintigraphy are promising (Schteingart et al. 2005). Maurea et al. (2001) have contacted a study which aim was to evaluate the role of radionuclide imaging in the characterization of non-hypersecreting adrenal masses. None of the patients, in their study, was hypersecreting or had symptoms of hypersecretion. They have concluded that “in patients with non-hypersecreting adrenal masses, radionuclide adrenal imaging, using spe- cific radiopharmaceuticals such as nor-cholesterol, MIBG, and FDG, may provide significant functional information for tissue characterization.
Radionuclide adrenal imaging performed with specifically labelled radiopharmaceuticals that target elements of adrenal function may provide specific metabolic information for lesion characterization, thus complementing morphological imaging modali- ties (Maurea et al. 2001). Several radiotracers that dis- play unique biological behavior may be used in nu- clear medicine for adrenal tumor evaluation. These tracers include labeled nor-cholesterol for cortical ad- enomas (Francis et al. 1992), metaiodo-benzylguani- dine (MIBG) (Francis et al. 1992) and hydroxyephed- rine (Shulkin et al. 1992) for medullary chromaffin tissue lesions, including pheochromocytomas and ganglioneuromas, and 18F-FDG (Boland et al. 1995) and 67Ga (Truong et al. 1997) for malignant tumors.
Molecular engineering has led to the synthesis of peptides of variable forms and sizes for tumor imag- ing (Fischman et al. 1993). In particular, radiolabeled somatostatin analogs have been proposed in the di- agnostic evaluation of several tumors (Lamberts et al. 1991). Among these, malignant adrenal masses showed significant uptake of somatostatin analog, suggesting the presence of somatostatin receptors (Maurea et al. 1996).
Professor Simone Maurea (personal communica- tion) has proposed to select nor-cholesterol in patient with incidentalomas and no history of malignancies; as second choice, in case of no nor-cholesterol uptake by the tumor, he suggests to use MIBG; conversely, in patients with malignancies and AIs, he proposes FDG-PET imaging.
Therefore, adrenal scintigraphy is recommended for tumor diagnosis and hence, for appropriate treat- ment planning, particularly when CT or MRI find- ings are inconclusive for lesion characterization” (Maurea et al. 2001). Both radiological and scinti- graphic imaging methods of the adrenal glands are necessary and therefore, should be considered com- plementary (Kurtaran et al. 2002).
Adenoma
It is important to emphasize that imaging cannot reliably distinguish between functioning and non- functioning adrenal adenomas (Mantero et al. 2000). In an Italian study (Mantero et al. 2000), the majority of the cortical adenomas were nonfunctioning 69%, whereas 25% secreted cortisol in slight excess, and 6% secreted aldosterone.
Ultrasound. Adenomas are uniformly hypoechoic (relative to the fat) (Conder et al. 2009) with smooth margins and a round to oval shape, although some le- sions have scalloped borders (polycyclic). Adenomas occasionally have an inhomogeneous appearance (Nurnberg et al. 2011). Because the masses are small, located deep within the abdomen, and surrounded by fat, they are often difficult to detect with U/S (Allo- lio 2001). Hormone-producing adrenal tumors, such as adenoma in Conn’s syndrome or hyperplasia in Cushing syndrome, are generally too small to be de- tectable by U/S (Hofer 1999).
CT. They are usually homogeneous, round and small, and have smooth borders and well delineated margins that separate them from adjacent structures (Thompson and Young Jr 2003). Attenuation values of <10 HU on an unenhanced CT are practically di- agnostic for adenomas (Ilias et al. 2007). A low (<10 HU) density means that the lipid fraction of the tu- mor is high, which is characteristic of lipid-rich mild adenomas (Papierska et al. 2013). However, approxi- mately 30% of adenomas are lipid poor adenomas and they are characterized by high initial density (usually up to 20 HU and in some cases up to 30 HU) (Papierska et al. 2013). Density assessment following i.v. contrast administration is necessary in such cases. Moderate enhancement, followed by a rapid contrast agent washout from the tumor occurs in adenomas (Papierska et al. 2013). An absolute contrast wash- out of >60% and a relative contrast washout of >40% characterize an adenoma with a sensitivity and speci- ficity of 98% and 92%, respectively (Dunnick and Ko- robkin 2002; Szolar et al. 2005).
MRI. On MRI, adenomas appear homogeneous on all sequences (Ilias et al. 2007). Their contrast en-
hancement is mild; they have low or equal signal in- tensity to the liver on T2-weighted images and may appear of lower signal intensity than the rest of the adrenal gland (Thompson and Young Jr 2003; Ilias et al. 2007). MRI also makes use of the lipid content of adenoma. In-phase and out-of-phase imaging dem- onstrates a loss of signal in a lipid-rich adenoma, on the out-of phase image compared with the cor- responding in-phase imaging. A metastatic deposit does not demonstrate this loss of signal (Conder et al. 2009).
Scintigraphy. If PET/CT is performed, most ma- lignant lesions will show avidity for 18F-FDG and most benign lesions will not (Boland 2011). In a study by Launay et al. (2015), they found that on 18F-FDG PET/CT, maximum standardized uptake values (SUV max) were significantly lower for adenomas (3.24) than for metastases (7.56) (p<0.05) (Launay et al. 2015).
Pheochromocytoma
Pheochromocytomas and paragangliomas are neural crest cell tumors associated with catechol- amine production and assessed by a metanephrines, nor-metanephrines measurements (Mittendorf et al. 2007; Pacak and Wimalawansa 2015).
Ultrasound. Only clinically manifest pheochro- mocytomas are often already several centimeters in size and can be sonographically detected in 90% of cases (Hofer 1999).
Pheochromocytoma may be visible as a well-de- fined mass, which may be solid or cystic to variable degrees. Echogenicity will be variable (Bowerman et al. 1981). On ultrasound, pheochromocytomas have a variable appearance ranging from solid (75% in one case series) to mixed cystic and solid to cystic (Bow- erman et al. 1981).
Gray-scale ultrasound is helpful in confirming cystic-necrotic change within a pheochromocytoma. The cystic fluid may be anechoic or contain echogenic debris while posterior acoustic enhancement may be an accompanying feature (Bowerman et al. 1981). Acute hemorrhage in a pheochromocytoma may ap- pear echogenic (Defechereux et al. 2002).
CT. Pheochromocytomas are often well-defined masses with attenuation values similar to those of muscle tissue, measuring approximately 30-40 HU (Miyake et al. 1989).
Pheochromocytoma may have attenuation values less than 10 HU and may display more than 60% washout of contrast agents on delayed scanning. Ad- renal pheochromocytomas should be included with adenomas in the differential diagnosis both for mass-
es with low attenuation on unenhanced CT and for lesions exhibiting a high percentage of contrast wash- out (Blake et al. 2003).
Szolar et al. (2005) have conducted a retrospect study to retrospectively measure the adrenal gland attenuation and the percentage loss of adrenal gland enhancement at delayed contrast medium-enhanced CT in patients with ACC and pheochromocytoma and to compare these data with those in patients with adenomas and metastases. They have concluded that “the enhancement loss in adrenocortical carcinomas and pheochromocytoma is similar to that in adrenal metastases but significantly less than that in adrenal adenomas”. The percentage change in contrast ma- terial washout is a useful adjunct to absolute CT at- tenuation values in differentiating adrenal adenomas from adrenocortical carcinomas and pheochromocy- tomas (Szolar et al. 2005).
Small neoplasms tend to be solid, whereas large le- sions are often cystic or hemorrhagic (Melicow 1977). Non-secreting pheochromocytoma tends to be larger than secreting ones (Newhouse et al. 1999). Cystic degeneration may be so marked that only a thin rim of identifiable cells may remain to disclose the true nature of the lesion.
I.V. administration of non-ionic contrast mate- rial for CT is a safe practice for patients with pheo- chromocytoma and related tumors even without al- blocking medication (Bessell-Browne and O’Malley 2007).
MRI. Adrenal pheochromocytomas have signal intensity on MRI T1 sequences equal to or higher than that of the liver, kidney and muscle (Mayo- Smith et al. 2001). Pheochromocytomas have higher signal intensity than that of fat on T2W sequences. This characteristic finding is due to the hypervascu- larity of the tumors (Ilias et al. 2007). Another reason is that of increased water content either in the cys- tic or in the liquefactive necrotic tumor (Leung et al. 2013). After contrast administration, pheochromocy- tomas enhance avidly and have a prolonged contrast washout phase. In heterogeneous tumors, the viable areas of the tumor enhance whilst necrotic areas do not (Ilias et al. 2007).
Scintigraphy. I131 MIBG and In111 octreotide are the two radiopharmaceuticals used to evaluate for a pheochromocytoma (Mayo-Smith et al. 2001). I131 MIBG is a structural analog of norepinephrine, which is stored in neurosecretory granules of the adrenal medulla (Mayo-Smith et al. 2001). Fiebrich et al. (2009) have investigated the sensitivity of 18F- DOPA PET, compared with 123I-MIBG scintigra- phy and computer tomography (CT)/MRI for tumor
localization in patients with catecholamine excess, they concluded that in order to localize tumors caus- ing catecholamine excess, 18F-DOPA PET is superi- or to 123I-MIBG scintigraphy and CT/MRI (Fiebrich et al. 2009).
Malignant
Adrenals may be the site of either primary or metastatic tumors from other organs. Lung, breast, stomach, and kidney cancers, melanomas, and lym- phomas most commonly metastasize to the adrenal gland (Lam and Lo 2002). While primary tumors of the adrenals are rare in adults, metastases to the ad- renal glands may occur in up to 33% of patients with bronchogenic carcinoma (Forsythe et al. 1977).
In patients with a known malignancy, the likeli- hood of an adrenal nodule being malignant is ap- proximately 25-36%. However, in the population without a known malignancy, the prevalence is less than 0.5% (Herrera et al. 1991; Gajraj and Young 1993; Lee et al. 1998; Song et al. 2008; Willatt et al. 2015).
On the other hand, metastatic lesions not grow- ing for 3 years were described (Papierska et al. 2013). Furthermore, 5-25% of mild lesions grow signifi- cantly larger during 1-year observation according to various data (Papierska et al. 2013).
Adrenal carcinomas occur more commonly in the left gland than the right, and up to 10% may be bilateral. They are usually quite large at presenta- tion, although a tumor as small as 1 cm has been reported (Dunnick 1990).
Ultrasound. In the presence of neoplastic in- volvement, however, ultrasound is of significant val- ue in the detection of mass lesion (Anderson 1971).
Because adrenal metastases are often necrotic, they may occasionally be confused with fluid-filled masses such as adrenal cysts. This distinction can usually be made by careful observation of the inter- nal echo content of the mass. Low-level echoes will be seen with adrenal metastases, whereas no inter- nal echoes can be seen within an uncomplicated ad- renal cyst (Hofer 1999).
Whether a suprarenal space-occupying lesion is malignant cannot be deduced from the lesion’s echogenicity (Nurnberg et al. 2011). Metastasis and carcinoma are regularly hypovascularized (Nurn- berg et al. 2011).
CT. When an adrenal mass has malignant mor- phologic features, such as an irregular margin and heterogenous density with a thick enhancing rim, at presenting contrast-enhanced CT, it likely repre-
sents a malignant lesion. The remaining morpho- logic features, including a smooth margin and ho- mogeneous density, can be seen in both benign and malignant disease, and are not sufficient for charac- terization of adrenal masses particularly in patients with a known history of malignancy (Song et al. 2008). On unenhanced CT, adrenal metastases usu- ally have attenuation values >10 HU (Young Jr 2007). In patients with metastases from melanoma, attenu- ation values may be lower (Rajaratnam and Waugh 2005). There is central area of low density owing to necrosis. It may be calcifications and areas of hem- orrhage. There is irregular peripheral enhancement following contrast (Conder et al. 2009). Large ne- crotic areas in a lesion usually signify malignancy. Conversely, metastases, when detected, are often homogeneous and similar in appearance to ad- enomas, especially when small (Boland et al. 2008).
MRI. The mix of hemorrhage and necrosis results in heterogeneous signal on both T1W and T2W imaging and irregular peripheral enhancement (Dunnick and Korobkin 2002; Conder et al. 2009). Differentiation between incidental adenomas and metastases can be conclusively achieved only when the primary neoplasm can also be imaged and dis- plays high signal intensity on T2W mages (Reinig et al. 1986). MRI should be performed in large tu- mours prior to surgery to assess vascular invasion (Schteingart et al. 2005).
Cysts
Adrenal cysts are uncommon lesions, and few reports about their CT appearance can be found in the literature. Adrenal cysts show a 3:1 female pre- dilection. Four types of cysts are recognized based on pathologic classification: endothelial, epithelial, parasitic, and posttraumatic pseudocysts (Cheema, et al. 1981).
Ultrasound. Cysts in ultrasounds show a cystic suprarenal mass. Unlike renal cysts, adrenal cysts often exhibit a thick wall. Cysts do not show Color Doppler-signals, only in border areas, which also ap- plies to hematoma or abscesses. Pseudocysts also may have internal septa. If a soft-tissue mass like compo- nent is present, surgery may be required to exclude a neoplasm (Goldman et al. 1996; Russell et al. 2000; Dunnick and Korobkin 2002; Young Jr 2007).
CT. Most adrenal cysts, owing to their uniform and homogeneous nature, can be characterized mor- phologically, although some can be complex and are occasionally confused with necrotic adrenal carcino- mas (Papierska et al. 2013). A small adrenal cyst with
near-water attenuation and a thin (≤3 mm) wall is likely to be benign (Korobkin 2000). In unenhanced CT, they demonstrate <10 HU, in 15-min CT cysts do not enhance (Boland et al. 2008).
MRI. They demonstrate high Signal Intensity in T2-weighted images (Boland et al. 2008).
Addison disease and Cushing syndrome
In Addison disease, there is adrenal atrophy not detectable with ultrasound; possible calcifications as evidence of prior tuberculosis (Allolio 2001).
In Cushing syndrome, in 80% of cases, there is bilateral hyperplasia due to pituitary (75%) or para- neoplastic (5%) ACTH overproduction; hyperplasia is usually not detectable with ultrasound (Allolio 2001).
Primary aldosteronism (PA)
Primary hyperaldosteronism has historically been underdiagnosed as a cause of hypertension, but recent reportshighlightits ubiquitousnature with a prevalence of 5-10% in screened hypertensive patients. Of such patients, up to 62.5% have a potentially curable adeno- ma as the underlying etiology (Kahn and Angle 2010).
Causes of primary aldosteronism (Moraitis and Stratakis 2011; Turcios 2015) may be 1) bilateral id- iopathic hyperplasia (BIH) (60% of cases); 2) aldo- sterone-producing adenoma (APA) (35% of cases); 3) primary adrenal hyperplasia (2% of cases); 4) aldo- sterone-producing adrenocortical carcinoma (<1% of cases); 5) familial hyperaldosteronism (FH): a) gluco- corticoid-remediable aldosteronism (FH type I) (<1% of cases), b) FH type II (APA or BIH) (<2% of cases); 6) Ectopic aldosterone producing adenoma or carci- noma (<0.1% of cases).
Approximately 95% (Young 2007) of the patiets with primary hyperaldosteronism have either bilat- eral idiopathic hyperplasia (IHA) - optimally treated with mineralocorticoid receptor blockade - or a uni- lateral aldosterone-producing adenoma (APA) that may be treated with unilateral laparoscopic adrenal- ectomy (Young 2007; Funder et al. 2008; Young and Stanson 2009).
Adrenal venous sampling (AVS) is the criterion standard to distinguish between unilateral and bi- lateral adrenal disease in patients with primary al- dosteronism (Young and Stanson 2009). The use of AVS to distinguish between IHA and APA was first proposed by Melby et al. (1970). Radiology together with AVS are very important in the treatment PA as only patients with lateralized adrenal hypersecretion can be cured by unilateral adrenalectomy; hence, the
distinction between unilateral and bilateral aldoste- rone hypersecretion is the key. Ultrasounds are of no help since hormone-producing adrenal tumors, such as adenoma in Conn’s syndrome, are generally too small to be detectable by U/S (Hofer 1999). Accord- ing to the “Clinical Practice Guidelines” of the Endo- crine Society, it is recommended that all patients with PA undergo an adrenal CT scan as the initial study in subtype testing and to exclude large masses that may represent adrenocortical carcinoma (Funder et al. 2008). Most aldosterone-producing adenomas (APA) are less than 20 mm in diameter (White et al. 2008). APA may be visualized as small hypodense nodules, usually <2 cm in diameter on CT (Funder et al. 2008). It is mostly of an homogeneous structure. In IHA adrenal glands, they may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are almost always more than 4 cm in diameter, but occasionally smaller, and like most adrenocortical carcinomas, have a suspicious imaging phenotype on CT (Young 2007; Funder et al. 2008). The adrenal CT lacks the overall accuracy to distinguish between unilateral and bilateral dis- ease (Mattsson and Young 2006). On MRI, adeno- mas appear homogeneous on all sequences (Ilias et al. 2007). Their contrast enhancement is mild; they have low or equal signal intensity to the liver on T2- weighted images and may appear of lower signal in- tensity than the rest of the adrenal gland (Thompson and Young 2003; Ilias et al. 2007). MRI also makes use of the lipid content of adenoma. In-phase and out-of-phase imaging demonstrates a loss of signal in a lipid-rich adenoma, on the out-of-phase image compared with the corresponding in-phase imaging. A metastatic deposit does not demonstrate this loss of signal (Conder et al. 2009). Adrenal scintigraphy with 6-131Iodomethyl-19-norcholesterol (NP-59), introduced in 1977, currently, it is no longer used in most centers (Funder et al. 2008). On a PET/CT scan, most commonly using 18F-fluorode oxyglucose (18F FDG PET/CT), the vast majority of adenomas do not accumulate the radiopharmaceutical. According to meta-analyses, 18F FDG PET/CT scanning generally has a high sensitivity (97%) and specificity (91%) in distinguishing between a malignant and benign ad- renal lesion (Boland et al. 2011). In a recent study, Powlson et al. (2015) used the metomidate, as a po- tent ligand of CYP11B1 and CYP11B2, that can be C11H3-labelled as a PET tracer. They concluded that increasing experience with 11C-metomidate PET- CT supports its use as an adjunct to AVS when this has failed, is ambiguous, or cannot be undertaken (Powlson et al. 2015).
Other rare diseases of the adrenals
Myelolipoma. Myelolipomas are usually detected incidentally at CT, and although most are small, they can occasionally be large, hemorrhagic, or rarely, ex- tra adrenal (Boland et al. 2008). In ultrasound, my- elolipoma appears as a heterogeneous mass and it is a mix of fat and hematopoietic tissue (Conder et al. 2009). In CT, some myelolipomas are also large but are confidently recognized owing to the presence of macroscopic fat (Vella et al. 2001). Presence of fatty foci with an attenuation coefficient from less than - 30 HU to - 100 HU is characteristic of this mild tumor. Myelolipomas can also contain small calci- fications (Cyran et al. 1996; Adusumilli and Ram- chandani 2001). On MRI, there is loss of signal on fat-saturated MRI (Herr et al. 2014).
Lymphoma. Primary adrenal lymphoma is de- fined as malignant neoplastic proliferation of the lymphoid cells exclusively in the adrenal glands (Khurana et al. 2015). The adrenal region is a rare extra-nodal site of occurrence for lymphoma. Foci of lymphomatous infiltration have smooth borders and are hypoechoic. Differentiation is required from lym- phomas in the renal or splenic hilum. If invasion by lymphoma is suspected, other nodal stations should be scanned and commonly infiltrated organs (spleen, liver) should be closely scrutinized (Birnholz 1973; Block et al. 1975; Forsythe et al. 1977; Scully et al. 1978). Imaging features include total encasement of the adrenal gland from adjacent retroperitoneal dis- ease (making it hard to identify the adrenal gland) to smaller discrete masses or diffuse enlargement. Bilateral metastatic involvement occurs in up to 50% of cases (Boland et al. 2008). Secondary involvement of the adrenal gland occurs in 4% of cases of non- Hodgkin lymphoma at CT and 25% in post-mortem studies (Zhou et al. 2012; Herr et al. 2014).
Other very rare adrenal disease is neuroblastoma, which is more common in children, usually has large size. On CT, it demonstrates >10 HU. More than 10 HU demonstrates also other very rare adrenal le- sions, such as ganglioneuroma, hemangioma, gran- ulamas (Boland et al. 2008).
Hemorrhage
Adrenal hemorrhage (AH) is a rare clinical entity that may present as an AI. AH is a heterogeneous entity that occurs in the postoperative period, in the antiphospholipid-antibody syndrome, in heparin- associated thrombocytopenia, or in the setting of se- vere physical stress and multiorgan failure (Vella et
al. 2001). Standard laboratory evaluation is not help- ful in establishing the diagnosis.
In a study on AH by Vella et al. (2001), of the 141 cases of AH, 78 were bilateral, and 63 were unilateral. A serum cortisol level of more than 18 µg/dl is often used to exclude adrenal insufficiency in situations of severe stress. Abdominal CT is probably the most re- liable and widely available method for detecting AH (Vella et al. 2001). Normal findings on abdominal CT early in the clinical course do not completely rule out the presence of hemorrhage, and repeated scans are justified if clinical suspicion is high. Bedside ultra- sonography may be appropriate in a critically ill im- mobile patient.
Ultrasound is the modality of choice for further evaluation of neonatal hematoma, and MRI is help- ful for further characterization (Westra et al. 1994). Whereas tumors distort adrenal shape, the normal triangular configuration of the gland is usually pre- served in cortical hemorrhage (Westra, et al. 1994). It is frequently discovered as an incidental finding at U/S performed for other reasons (Willemse et al. 1989; Kawashima et al. 1999). CT and MRI (Westra et al. 1994) are usually not required, except when the mass remains solid in appear over time or enlarges and coexisting neuroblastoma needs to be ruled out. Usually, the hemorrhage resolves completely, but it may calcify at its periphery, as seen incidentally on plain abdominal radiographs (Barzon et al. 2003).
Tumor size
In an Italian study, they found that adenomas were significantly smaller than carcinomas (3.5, range from 1-15 vs. 7.5, range from 2.6-25 cm; p<0.001), and a cut-off at 4.0 cm had the highest sensitivity (93%) in differentiating between benign and malignant tu- mor (Mantero et al. 2000). According NIH Statement (2002), they recommend that “patients with tumors greater than 6 cm usually are treated surgically, while those with tumors less than 4 cm are generally moni- tored. In patients with tumors between 4 cm and 6 cm, criteria in addition to size should be considered in making the decision to monitor or proceed to ad- renalectomy (NIH 2002).
Natural history
Concerning the natural history of AIs, the risk of malignancy over time for masses defined as benign at diagnosis is estimated at about 1/1000, even though 5-25% of masses increase in size during follow-up (Barzon et al. 2003). Hyperfunction develops in about
1.7% of cases and the risk is higher in patients with le- sions larger than 3 cm (Barzon et al. 2003). Cortisol hypersecretion is the most likely disorder that may ensue, and it remains subclinical in about two-thirds of cases (Bulow et al. 2006).
In a Swedish prospective study, patients with AI had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period (Cho et al. 2013). In a Korean Study based on their findings, initial hormonal and radiographic evalua- tions for AIs appear to be more important than fol- low-up tests because functional or malignant changes are rare (Fontana et al. 1999).
Fontana et al. (1999) evaluating the role of ultraso- nography in the follow-up of AIs found that at diag- nosis, U/S was not sufficiently reliable in evaluating adrenal mass characteristics. Considering the high correlation between U/S and CT size estimation, in the case of a presumably benign lesion, U/S could be considered a simple, economic, and effective method of follow-up, with CT limited to evaluating masses growing over time (CT remains mandatory at diag- nosis) (Fontana et al. 1999).
According to the recommendation of the “AACE and AAES, Medical Guidelines for the Management of Adrenal Incidentalomas”; patients with AIs who do not fulfil the criteria for surgical resection need to have radiographic revaluation at 3 to 6 months and then annually for 1 to 2 years. For all adrenal tumors, hormonal evaluation should be performed at the time of diagnosis and then annually for 5 years.
Conclusions
We propose the following step-by-step approach to AI:
1. If AI was discovered by ultrasound, proceed with CT scan and biochemical tests. If AI was discov- ered by C,T proceed with biochemical tests and further study of CT. These are described below.
2. We proceed at the same time with biochemical tests. These are overnight dexamethasone (1 mg) suppression test; measurement of plasma by el- evated plasma fractionated metanephrines or el- evated 24 h urinary fractionated metanephrines (Mittendorf et al. 2007). If hypertension present, proceed to measurement of the plasma aldoste- rone concentration and plasma renin activity (Young Jr 2007).
3. If positive, proceed to confirmation of autono- mous secretion of cortisol, aldosterone, or cate- cholamines to avoid false positive results (Young Jr 2007) and if these are also positive, consider
surgery. If there is lack of autonomous secretion of cortisol, aldosterone or catecholamines or neg- ative results, then proceed with imaging pheno- type (Young Jr 2007).
4. A) If less than 4 cm and if attenuation values of <10 HU on an unenhanced CT, this is practically diagnostic for adenomas (Ilias et al. 2007). In ad- dition to these, and if it has benign characteris- tics such as homogeneous, round and small, has smooth borders and well delineated margins that separate them from adjacent structures (Thomp- son and Young Jr 2003), then we can safely diag- nose an adenoma. B) Repeating imaging at 6, 12, and 24 months and repeating hormonal testing annually for 4 years (Young Jr 2007).
5. If size >4 cm or HU >10 or non-benign imaging characteristics of the tumor, consider surgery.
6. If during follow up either growth ≥1 cm or autono- mous hormonal secretion, then consider surgery.
7. If HU as low as -20 to -100 diagnose myelolipo- ma and proceed as 4B above.
8. If the unenhanced CT is more than 10 HU and in terms of the tumor nature (adenoma or “non- adenoma”), primary localization (e.g. liver hilar tumor, pancreatic tumors), and infiltration of the surrounding tissues then we proceed with ex- amination with contrast medium administration (washout assessment) (Bednarczuk et al. 2016). In comparison to unenhanced CT, based on this ex- amination it is possible to assess the absolute and relative washout values features of the surround- ing tissues infiltration, as well as the presence of liver metastases (Bednarczuk et al. 2016).
9. An absolute contrast washout of >60% and a rela- tive contrast washout of >40% characterize an adenoma with a sensitivity and specificity of 98 and 92% respectively (Dunnick and Korobkin 2002; Szolar et al. 2005).
10. If washout <50% then there is a non adenoma le- sion (Bednarczuk et al. 2016).
11. Suspicion for carcinomas increases, if the at- tenuation on unenhanced studies is higher than 10 HU (Ilias et al. 2007; Young Jr 2007). On contrast-enhanced studies, carcinomas enhance avidly due to their vascularity. The pattern of en- hancement can be homogeneous, unless there is central necrosis (Dunnick and Korobkin 2002; Lockhart et al. 2002; Ilias et al. 2007; Young Jr 2007). The relative percentage washout of carci- nomas is <40% (Slattery et al. 2006).
12. If either steps 10 or 11 above then consider either A or B below: A) Fine-needle aspiration biopsy if metastatic disease or infection suspected, or
surgery or close follow-up (e.g., repeating imag- ing at 3 months). Before fine-needle examina- tion, pheochromocytoma must be excluded. B) Repeating imaging at 6, 12, and 24 months. Re- peating hormonal testing annually for 4 years. Surgery if mass is >4 cm in diameter (Young Jr 2007).
13. If AI was discovered by MRI, then MRI can also be used to diagnose lipid rich adrenal adenomas using the dual gradient echo sequence (Willatt et al. 2015). In the case that AI is discovered by MRI, also, do steps 2, 3 above.
14. If an adrenal nodule loses signal on opposed im- aging in comparison with in-phase imaging, then it can be declared an adenoma (Fujiyoshi et al. 2003; Willatt et al. 2015). More often than not, this is seen with the naked eye. However, for cas- es that are more equivocal, a threshold of 16.5% signal loss can be used (Caoili et al. 2000; Willatt et al. 2015). This is known as the signal intensity index.
15. Chemical shift MRI (CS-MRI) is more sensitive than unenhanced CT for intracytoplasmic lipid content and can diagnose many of the nodules which demonstrate HU of between 10 and 30 as lipid rich adenomas (Haider et al. 2004; Willatt et al. 2015).
16. The pheochromocytomas have very high signal intensity on T2-weighted (T2W) images, higher than adenoma or metastasis, and usually iso- or hypointense on T1-weighted imaging. Strong enhancement, which may be heterogeneous de- pending on the degree of cystic change (Conder et al. 2009).
17. In adrenocortical carcinoma, the mix of hemor- rhage and necrosis results in heterogeneous sig- nal on both T1W and T2W imaging and irregu- lar peripheral enhancement (Conder et al. 2009).
18. MRI should be performed in large tumors prior to surgery to assess vascular invasion.
19. If there is suspicion for pheochromocytoma, and CT or MRI are not conclusive, you may consider either I131 MIBG or In111 octreotide (Mayo- Smith et al. 2001).
20. If there is problem in localization of a pheochro- mocytoma then 18F-DOPA PET is superior to 123I-MIBG scintigraphy and CT/MRI (Fiebrich et al. 2009).
Acknowledgement
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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