Adrenal Mass Evaluation

Adrenal Mass Evaluation. This allows for initial attenuation measurement of the mass. If diagnostic benign imaging characteristics are not present, a contrast-enhanced series can be performed between 60 and 90 seconds after the administration of intravenous (IV) contrast followed by a 15-minute delayed-phase imaging for evaluation of washout characteristics [15,16]. A study that substituted a 10-minute delayed-phase scan was found to have diminished sensitivity to adenomas compared with a 15-minute delay and is not generally utilized [15]. MRI MR chemical shift imaging (CSI) relies on differences in fat and water molecule precession frequencies and consists of T1-weighted in-phase and opposed-phase dual-echo gradient-recalled echo sequences when both echoes are obtained in the same breath hold. The opposed-phase echo is obtained before the in-phase echo, and lesions with intracytoplasmic fat will be detected by signal intensity loss when opposed-phase images are compared with in- phase images [17]. If MR-CSI is indeterminate, the addition of dynamic postcontrast imaging without or with the addition of T2-weighted imaging has been shown to aid in the diagnosis of adenoma [18-20]. Molecular Imaging PET can be utilized for evaluation of different adrenal abnormalities. Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET can detect hypermetabolic metastatic lesions. Patients are required to fast for 4 to 6 hours prior to injection of FDG, and data are acquired approximately 60 to 120 minutes after injection. A CT or MRI, respectively, is obtained and a PET scan that covers the same field of view. Co-registered images are then displayed on a workstation for analysis [21]. FDG, 18-F-dihydroxylphenylaalanine (DOPA), Ga-68-DOTATATE, or I-123 metaiodobenzylguanidine (MIBG) can be utilized to identify hyperfunctioning tumors, such as pheochromocytoma.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. FDG-PET/CT is a modality that can further characterize whether a mass is benign versus malignant, as malignant lesions have increased metabolic activity and, therefore, increased glucose avidity compared with benign lesions. Both qualitative and quantitative assessment using standard uptake values (SUVs) is performed to evaluate a lesion. Malignant lesions show increased activity compared with benign lesions with a sensitivity between 93% and 100% [22]. If pheochromocytoma is suspected, then FDG, DOPA, DOTATATE, or MIBG studies can be utilized to improve detection when anatomic localization is inconclusive, to identify additional lesions in the setting of hereditary disease, or to evaluate for metastatic disease [23]. Discussion of Procedures by Variant Variant 1: Indeterminate adrenal mass, less than 1 cm on initial imaging. No diagnostic benign imaging features. No history of malignancy. For patients with no prior history of malignancy and an incidentally detected adrenal mass <1 cm without diagnostic benign imaging characteristics on initial study, the mass is most likely benign [12,24]. One study by Herrera et al [5] examined 342 patients without a history of malignancy and found that the rate of malignancy in adrenal nodules was only 1.5% and that all malignant lesions were >5 cm. Although many guidelines exist regarding the appropriate time interval for follow-up of adrenal nodules, no agreement has been achieved. Stability of a lesion should be assessed by repeat imaging for nodules >1 cm, but there is no literature supporting further evaluation of lesions <1 centimeter. CT Abdomen For lesions <1 cm and no history of malignancy, there is no primary evidence supporting the use of CT for initial evaluation. Metastatic disease to the adrenal gland without a known history of primary malignancy is unusual [4,5]. In a study of 1,049 incidental adrenal masses in patients with no known history of cancer, none were malignant.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. The majority of lesions were adrenal adenomas, myelolipomas, and cysts [6]. FDG-PET/CT Skull Base to Mid-Thigh For lesions <1 cm and no history of malignancy, there is no primary evidence supporting the use of FDG-PET/CT for initial evaluation. Metastatic disease to the adrenal gland without a known history of primary malignancy is unusual [4,5]. In a study of 1,049 incidental adrenal masses in patients with no known history of cancer, none were malignant. The majority of lesions were adrenal adenomas, myelolipomas, and cysts [6]. Adrenal Mass Evaluation It is recognized that FDG-PET is less sensitive and specific for lesions <10 mm [25], and although PET has the potential to detect very small adrenal metastases, one study showed that 2 of 5 lesions that proved to be false- negative for malignancy on PET were <10 mm [26]. Therefore, the specificity of FDG-PET for characterizing adrenal lesions <10 mm may be limited. Image-Guided Biopsy Adrenal Gland For lesions <1 cm and no history of malignancy, there is no primary evidence supporting the use of biopsy for initial evaluation [27-30]. MRI Abdomen For lesions <1 cm and no history of malignancy, there is no primary evidence supporting the use of MRI for initial evaluation. Metastatic disease to the adrenal gland without a known history of primary malignancy is unusual [4,5]. In a study of 1,049 incidental adrenal masses in patients with no known history of cancer, none were malignant. The majority of lesions were adrenal adenomas, myelolipomas, and cysts [6]. Variant 2: Indeterminate adrenal mass, 1 to 2 cm on initial imaging. No diagnostic benign imaging features. No history of malignancy. Follow-up imaging in 12 months. For patients with no prior history of malignancy and an incidentally detected adrenal mass between 1 and 2 cm without diagnostic benign imaging characteristics on initial study, the mass is most likely benign [12,24].


Adrenal Mass Evaluation

Adrenal Mass Evaluation. One study by Herrera et al [5] examined 342 patients without a history of malignancy and found that the rate of malignancy in adrenal nodules was only 1.5% and that all malignant lesions were >5 cm. In another series of 887 patients who had adrenal incidentalomas, a diameter of >4 cm was shown to have 90% sensitivity for the detection of adrenocortical carcinoma but low specificity; only 24% of lesions >4 cm in diameter were malignant [27]. Although many guidelines exist regarding the appropriate time interval for follow-up, no agreement has been achieved. Stability of a lesion >1 cm should be assessed by repeat imaging. If prior imaging is or becomes available or a lesion has been stable for 1 year or more, it can generally be considered benign and no additional imaging follow-up is required; however, imaging may be performed per clinical discretion [13,31]. Therefore, in this clinical scenario, follow-up adrenal-specific imaging can be considered at 12 months to ascertain whether there are benign imaging features and ensure the mass is stable in size. Although both benign and malignant adrenal masses can enlarge over time, interval growth of adrenal masses has been advocated as a potential indicator of malignancy. However, there is scant information on what size change over what time interval requires further investigation. A study has shown that a growth of 0.8 cm on follow-up CT had the highest combination of sensitivity (72%) and specificity (81%) when evaluating absolute size change, growth rate, and growth percent in 111 benign and 25 malignant pathologically proven adrenal lesions. Although the unadjusted odds ratio for this threshold was 11.02, no threshold was found with 100% sensitivity or specificity [32]. Another study of 105 adenomas and 26 malignant nodules found that approximately one-third of adenomas grew, all at a rate of <0.3 cm/year, whereas all malignant nodules grew at a rate of >0.5 cm/year [33].


Adrenal Mass Evaluation

Adrenal Mass Evaluation. CT Abdomen Evaluation of an adrenal mass indeterminate on initial imaging consists of an adrenal CT protocol. Unenhanced thin-section images through the upper abdomen are obtained and then reviewed to evaluate for diagnostic benign imaging features. Some benign lesions, such as cysts and myelolipomas, are readily characterized by CT. Adrenal adenomas contain lipid to varying degrees, and this lowers their attenuation coefficient on unenhanced CT. A threshold value of 10 HU is generally accepted as a cutoff value for diagnosing a lipid-rich adenoma, as the 10 HU threshold has a sensitivity of 71% and specificity of 98% for adenomas [34]. As the threshold value for the HU unit cutoff is increased (for example from 0 to 10 HU), the sensitivity for adenomas increases; however, so does the false-positive rate [35,36]. Lesions that do not contain intracellular lipid (adenoma) or macroscopic fat (myelolipoma) on CT are evaluated with pre- and postcontrast imaging. If there is no enhancement, the lesion may be characterized as a benign lesion such as a cyst or hemorrhage. The use of washout CT may increase the accuracy of characterization compared with MRI. In one small study, washout CT was slightly superior to MR-CSI in characterizing adrenal masses that measured >10 HU on unenhanced CT [42]. Another study demonstrated that washout CT is more accurate than MR-CSI characterization of hyperattenuating adrenal masses, regardless of history of malignancy [43]. Routine abdominal CT without IV contrast will often provide definitive evidence of adenoma. Routine abdominal CT with IV contrast is rarely diagnostic and should not be considered for characterization of a known adrenal lesion. FDG-PET/CT Skull Base to Mid-Thigh For lesions measuring 1 to 2 cm and no history of malignancy, there is no primary evidence supporting the use of FDG-PET/CT for initial evaluation. Metastatic disease to the adrenal gland without a known history of primary malignancy is unusual [4,5].


Adrenal Mass Evaluation

Adrenal Mass Evaluation. In a study of 1,049 incidental adrenal masses in patients with no known history of cancer, none were malignant. The majority of lesions were adrenal adenomas, myelolipomas, and cysts [6]. SUVs are typically greater for metastatic disease [21]. However, mild activity can be seen in benign adenomas (typically less than background liver), thus potentially leading to false-positive interpretations. Studies have predominantly evaluated FDG-PET or FDG-PET/CT in patients with cancer. However, Tessonnier et al [44] evaluated 41 adrenal tumors in 37 patients who had no history of malignancy using FDG-PET/CT. All tumors were without diagnostically benign features on CT or MRI. In this small series, a tumor/liver SUVmax ratio >1.8 yielded 100% sensitivity and specificity for malignancy. It is recognized that FDG-PET is less sensitive and specific for lesions <10 mm [25], and although PET has the potential to detect very small adrenal metastases, one study showed that 2 of 5 lesions that proved to be false- negative for malignancy on PET were <10 mm [26]. Therefore, the specificity of FDG-PET for characterizing adrenal lesions <10 mm may be limited. Image-Guided Biopsy Adrenal Gland For lesions measuring 1 to 2 cm and no history of malignancy, there is no primary evidence supporting the use of biopsy for initial evaluation [27-30]. Most studies on the efficacy of adrenal biopsy have been performed in a mixed population of patients. Biopsy samples insufficient to make a diagnosis are obtained in 4% to 19% (mean = 15%) of cases [7,45-47]. When sufficient material is obtained, the accuracy of biopsy is between 96% and 100% for malignant lesions. In one study, rates of positive biopsy in three groups with prior diagnosis of cancer, those with previously undiagnosed cancer with simultaneous masses suspicious for metastases, and those with isolated incidentalomas showed positive biopsy results of 70.6%, 69.0%, and 16.7%, respectively. In all three groups, size was a significant predictor of malignancy.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. Benign incidentalomas in all three groups had a mean measurement of 2.1 cm, and malignancies had a mean measurement of 9.3 cm [48]. Fine-needle aspiration alone cannot reliably be used to differentiate adrenocortical carcinoma from adrenal adenoma. In addition, the sensitivity of needle biopsy for adrenocortical carcinoma is low. In one study, the sensitivity of needle biopsy for detecting adrenocortical carcinoma was reported as 50% [48]. Another study reports the maximal sensitivity as 70% [49]. In addition, percutaneous biopsy of adrenal lesions is not without risk. Complication rates range from 8% to 12% and consist of bleeding, pneumothorax, infection, and anecdotes of tumor seeding of needle instability should a clinically unsuspected pheochromocytoma be biopsied. Careful correlation with clinical and endocrinological data is needed, combined with knowledge of other features, such as tumor size and imaging characteristics, to distinguish adenoma from carcinoma due to the possibility of sampling error. Thus, biopsy is better suited to a population with a high risk of malignant lesions and is most useful when noninvasive imaging studies are negative or inconclusive. MRI Abdomen Qualitative and quantitative MRI methods have been used to distinguish between adenomas and nonadenomas. An unenhanced MR-CSI (in-phase and opposed-phase gradient-echo scans) relies on differentiating lesions by their Adrenal Mass Evaluation relative lipid content, with malignant lesions having virtually no lipid [50]. This has been shown to be correct for 96% to 100% of cases, depending on the study [51,52]. However, these studies were performed in a mixed population of patients with regard to their history of malignancy, so results may not be directly applicable to populations either with or without known malignancy. Several other authors have shown excellent results in characterizing masses in populations with incidentally detected adrenal masses using simpler CSI techniques [53- 55].


Adrenal Mass Evaluation

Adrenal Mass Evaluation. In cases where the unenhanced CT measurement was between 10 and 30 HU (ie, indeterminate by CT), applying CSI can be discriminatory. In one study, 89% of adenomas with densities between 10 and 30 HU were correctly characterized by CSI [59]. Another study concluded that up to 60% of lesions misclassified by unenhanced CT attenuation measurements can be correctly characterized as adenomas by MR-CSI [53]. Gabriel et al [60] have demonstrated that even heterogeneous loss of signal is evidence of a benign lesion. Thus, MR-CSI may have better sensitivity and specificity than nonenhanced CT. Diffusion-weighted MRI techniques have been investigated in helping to distinguish benign and malignant masses in various organ systems. Neither Miller et al [61] nor Tsushima et al [62] found that this technique could differentiate adrenal adenomas and nonadenomas. A number of series have studied adrenal lesion amount of contrast enhancement and enhancement pattern on MRI after indeterminate MR-CSI [18-20]. In one series of 46 lipid-poor adrenal lesions, the combination of T2-signal intensity and contrast enhancement could identify adenomas with a sensitivity of 84% to 89%, specificity of 96%, and accuracy of 91% to 94% [20]. Additionally, MRI without and with IV contrast may be considered if there is concern for pheochromocytoma, as the contrast can show the typical bright enhancement of this lesion. Contrast can also confirm lack of enhancement of a cystic lesion. Variant 3: Indeterminate adrenal mass, greater than 2 cm and less than 4 cm on initial imaging. No diagnostic benign imaging features. No history of malignancy. Adrenal specific imaging. For patients with no prior history of malignancy and an incidentally detected adrenal mass without diagnostic benign imaging characteristics >2 cm and <4 cm, dedicated adrenal-specific imaging can be considered at the time of detection to determine if the mass can be diagnosed to be an adenoma [16,37,63].


Adrenal Mass Evaluation

Adrenal Mass Evaluation. If adrenal-specific imaging is nondiagnostic, a 6- to 12-month follow-up examination can be performed to document stability [12]. One study by Herrera et al [5] examined 342 patients without a history of malignancy and found that the rate of malignancy in adrenal nodules was only 1.5% and that all malignant lesions were >5 cm. In another series of 887 patients who had adrenal incidentalomas, a diameter >4 cm was shown to have 90% sensitivity for the detection of adrenocortical carcinoma but low specificity; only 24% of lesions >4 cm in diameter were malignant [27]. Although many guidelines exist regarding the appropriate time interval for follow-up, no true agreement has been achieved. Stability of a lesion should be assessed by repeat imaging, if possible in the same modality as initial imaging to allow for accurate comparison. If prior imaging is or becomes available or a lesion has been stable for 1 year or more, it can generally be considered benign, and no additional imaging follow-up is required [12,13]; however, it may be performed per clinical discretion. Although both benign and malignant adrenal masses can enlarge over time, interval growth of adrenal masses has been advocated as a potential indicator of malignancy. However, there is scant information on what size change over what time interval requires further investigation. A study has shown that a growth of 0.8 cm on follow-up CT had the highest combination of sensitivity (72%) and specificity (81%) when evaluating absolute size change, growth rate, and growth percent in 111 benign and 25 malignant pathologically proven adrenal lesions. Although the unadjusted odds ratio for this threshold was 11.02, no threshold was found with 100% sensitivity or specificity [32]. Adrenal Mass Evaluation CT Abdomen Evaluation of an adrenal mass indeterminate on initial imaging consists of an adrenal CT protocol.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. Unenhanced thin-section images through the upper abdomen are obtained and then reviewed to evaluate for diagnostic benign imaging features. Some benign lesions such as cysts and myelolipomas are readily characterized by CT. Adrenal adenomas contain lipid to varying degrees, and this lowers their attenuation coefficient on unenhanced CT. A threshold value of 10 HU is generally accepted as a cutoff value for diagnosing a lipid-rich adenoma, as the 10-HU threshold has a sensitivity of 71% and specificity of 98% for adenomas [34]. As the threshold value for the HU cutoff is increased (for example from 0 HU to 10 HU), the sensitivity for adenomas increases; however, so does the false-positive rate [35,36]. Lesions that do not contain intracellular lipid (adenoma) or macroscopic fat (myelolipoma) on CT are evaluated with pre- and postcontrast imaging. If there is no enhancement, the lesion may be characterized as a benign lesion, such as a cyst or hemorrhage. The use of washout CT may increase accuracy of characterization compared with MRI. In one small study, washout CT was slightly superior to MR-CSI in characterizing adrenal masses that measured >10 HU on unenhanced CT [42]. Another study demonstrated that washout CT is more accurate than MR-CSI characterization of hyperattenuating adrenal masses, regardless of history of malignancy [43]. Routine abdominal CT without IV contrast often will provide definitive evidence of adenoma. Routine abdominal CT with IV contrast is rarely diagnostic and should not be considered for characterization of a known adrenal lesion. FDG-PET/CT Skull Base to Mid-Thigh For lesions >2 cm and <4 cm and no history of malignancy, there is no primary evidence supporting the use of FDG-PET/CT for initial evaluation. Metastatic disease to the adrenal gland without a known history of primary malignancy is unusual [4,5]. In a study of 1,049 incidental adrenal masses in patients with no known history of cancer, none were malignant.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. The majority of lesions were adrenal adenomas, myelolipomas, and cysts [6]. SUVs are typically greater for metastatic disease [21]. However, mild activity can be seen in benign adenomas (typically less than background liver), thus potentially leading to false-positive interpretations. Studies have predominantly evaluated FDG-PET or PET/CT in the oncologic population. However, Tessonnier et al [44] used FDG-PET/CT to evaluate 41 adrenal tumors in 37 patients who had no history of malignancy, and all tumors were without diagnostically benign features on CT or MRI. In this small series, a tumor/liver SUVmax ratio >1.8, yielded 100% sensitivity and specificity for malignancy. In addition, it is recognized that FDG-PET is less sensitive and specific for lesions <10 mm [25]. In one study, 2 of 5 lesions that proved to be false-negative for malignancy on PET were <10 mm [26]. 11C-metomidate has been found to localize in adrenocortical tumors and is useful for determining whether a tumor is of adrenocortical origin. However, it cannot distinguish between benign and malignant tumors [64,65]. Image-Guided Biopsy Adrenal Gland For lesions >2 cm and <4 cm and no history of malignancy, there is no primary evidence supporting the use of biopsy for initial evaluation [27-30]. Adrenal Mass Evaluation malignancy. Benign incidentalomas in all three groups had a mean measurement of 2.1 cm, and malignancies had a mean measurement of 9.3 cm [48]. Fine-needle aspiration alone cannot reliably be used to differentiate adrenocortical carcinoma from adrenal adenoma. In addition, the sensitivity of needle biopsy for adrenocortical carcinoma is low. In one study, the sensitivity of needle biopsy for detecting adrenocortical carcinoma was reported as 50% [48]. Another study reports the maximal sensitivity as 70% [49]. In addition, percutaneous biopsy of adrenal lesions is not without risk.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. Complication rates range from 8% to 12% and consist of bleeding, pneumothorax, infection, and anecdotes of tumor seeding of needle instability should a clinically unsuspected pheochromocytoma be biopsied. Careful correlation with clinical and endocrinological data is needed, combined with knowledge of other features, such as tumor size and imaging characteristics to distinguish adenoma from carcinoma due to the possibility of sampling error. Thus, biopsy is better suited to a population with a high risk of malignant lesions and is most useful when noninvasive imaging studies are negative or inconclusive. MRI Abdomen Qualitative and quantitative MRI methods have been used to attempt to distinguish between adenomas and nonadenomas. MR-CSI (in-phase and opposed-phase gradient-echo scans) relies on differentiating lesions by their relative lipid content, with malignant lesions having virtually no lipid [50]. This has been shown to be correct for 96% to 100% of the cases, depending on the study [51,52]. However, these studies were performed in a mixed population of patients with regard to their history of malignancy, so results may not be directly applicable to populations either with or without known malignancy. Several other authors have shown excellent results in characterizing masses in populations with incidentally detected adrenal masses using simpler CSI techniques [53- 55]. In cases in which the unenhanced CT attenuation measurement was between 10 and 30 HU (ie, indeterminate by CT), applying CSI can be discriminatory. In one study, 89% of adenomas with densities between 10 and 30 HU were correctly characterized by CSI [59]. Another study concluded that up to 60% of lesions misclassified by unenhanced CT attenuation measurements can be correctly characterized as adenomas by MR-CSI [53]. Gabriel et al [60] have demonstrated that even heterogeneous loss of signal is evidence of a benign lesion. Thus, MR-CSI may have better sensitivity and specificity than nonenhanced CT.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. Whether diffusion-weighted MRI techniques are helpful in distinguishing benign and malignant masses in various organ systems has been investigated. Neither Miller et al [61] nor Tsushima et al [62] found that this technique could differentiate adrenal adenomas and nonadenomas. For the diagnosis of adenoma, contrast-enhanced MRI does not provide additional information beyond the unenhanced technique. However, MRI without and with IV contrast may be considered if there is concern for pheochromocytoma, as the contrast can show the typical bright enhancement of this lesion. Contrast can also confirm lack of enhancement of a cystic lesion. Adrenocortical carcinomas can be functioning or nonfunctioning. Those with nonfunctioning tumors most often present with a large mass and symptoms such as abdominal or flank pain. Because of the typically late presentation of nonfunctioning tumors, metastatic disease is common. For those smaller masses discovered incidentally and as functioning tumors, which most likely present with Cushing syndrome or virialization, metastatic disease at the time of presentation is less likely [66]. Adrenal Mass Evaluation One study by Herrera et al [5] examined 342 patients without a history of malignancy and found that although the rate of malignancy in all adrenal nodules was only 1.5%, all malignant lesions were >5 cm. In a series of 887 patients who had adrenal incidentalomas, a diameter >4 cm was shown to have 90% sensitivity for the detection of adrenocortical carcinoma but low specificity, as only 24% of lesions >4 cm in diameter were malignant [27]. In contrast, in patients with a history of malignancy, Candel et al [11] found that 87% of lesions <3 cm were benign and that >95% of lesions >3 cm were malignant. In a similar population, Lee et al [35] found that 79% of lesions <2.5 cm were benign. Van Erkel et al [67] in a mixed population showed that a threshold of 3.1 cm discriminated 93% of lesions.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. Studies have predominantly evaluated FDG-PET or FDG-PET/CT in the oncologic population. SUVs are typically greater for metastatic disease [21]. However, mild activity can be seen in benign adenomas (typically less than background liver), thus potentially leading to false-positive interpretations. However, Tessonnier et al [44] evaluated 41 adrenal tumors in 37 patients who had no history of malignancy using FDG-PET/CT. All tumors were without diagnostically benign features on CT or MRI. In this small series, a tumor/liver SUVmax ratio >1.8 yielded 100% sensitivity and specificity for malignancy. 11C-metomidate has been found to localize in adrenocortical tumors and is useful for determining whether a tumor is of adrenocortical origin. However, it cannot distinguish between benign and malignant tumors [64,65]. Fine-needle aspiration alone cannot reliably be used to differentiate adrenocortical carcinoma from adrenal adenoma. In addition, the sensitivity of needle biopsy for adrenocortical carcinoma is low. In one study, the sensitivity of needle biopsy for detecting adrenocortical carcinoma was reported as 50% [48]. Another study reports the maximal sensitivity as 70% [49]. In addition, percutaneous biopsy of adrenal lesions is not without risk. Complication rates range from 8% to 12% and consist of bleeding, pneumothorax, infection, and anecdotes of tumor seeding of needle tracts. Careful correlation with clinical and endocrinological data is needed, combined with knowledge of other features, such as tumor size and imaging characteristics, to distinguish adenoma from carcinoma due to the possibility of sampling error. Thus, biopsy is better suited to a population with a high risk of malignant lesions and is most useful when noninvasive imaging studies are negative or inconclusive. Adrenal Mass Evaluation Variant 5: Adrenal mass, less than 4 cm on initial imaging. No diagnostic benign imaging features. History of malignancy. Adrenal specific imaging.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. For patients with a history of malignancy and an adrenal mass >1 cm and <4 cm and no diagnostic benign imaging features on prior examinations or documented stability, adrenal-specific imaging should be performed. If adrenal- specific imaging does not characterize the lesion as benign or if the results are indeterminate, evaluation of other imaging features, such as presence of central necrosis and presence of irregular margins or thick enhancing rim, can indicate an increased likelihood of malignancy [74]. In these instances, adrenal biopsy or FDG-PET/CT should be considered for further evaluation [75]. In patients with a history of malignancy, Candel et al [11] found that 87% of lesions <3 cm were benign and that >95% of lesions >3 cm were malignant. In a similar population, Lee et al [35] found that 79% of lesions <2.5 cm were benign. Van Erkel et al [67] in a mixed population showed that a threshold of 3.1 cm discriminated 93% of lesions. CT Abdomen Evaluation of an adrenal mass indeterminate on initial imaging consists of an adrenal CT protocol. Unenhanced thin-section images through the upper abdomen are obtained and then reviewed to evaluate for diagnostic benign imaging features. Some benign lesions, such as cysts and myelolipomas, are readily characterized by CT. Adrenal adenomas contain lipid to varying degrees, and this lowers their attenuation coefficient on unenhanced CT. A threshold value of 10 HU is generally accepted as a cutoff value for diagnosing a lipid-rich adenoma, as the 10 HU threshold has a sensitivity of 71% and specificity of 98% for adenomas [34]. As the threshold value for HU unit cutoff is increased (for example from 0 to 10 HU), the sensitivity for adenomas increases; however, so does the false-positive rate [35,36]. Lesions that do not contain intracellular lipid (adenoma) or macroscopic fat (myelolipoma) on CT are evaluated with pre- and postcontrast imaging.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. If there is no enhancement, the lesion may be characterized as a benign lesion, such as a cyst or hemorrhage. Metastases from particular primary malignancies, namely hepatocellular carcinoma or clear-cell renal cell carcinoma, have been shown to mimic adenoma based on their washout values. In one study, 84% (16 of 19) of metastases from these two primary tumors would be falsely considered lipid-poor adenomas if washout characteristics alone were used [76]. The use of washout CT may increase accuracy of characterization compared with MRI. In one small study, washout CT was slightly superior to MR-CSI in characterizing adrenal masses measuring >10 HU on unenhanced CT [42]. Another study demonstrated that washout CT is more accurate than MR-CSI characterization of hyperattenuating adrenal masses, regardless of history of malignancy [43]. Routine abdominal CT without IV contrast often will provide definitive evidence of adenoma. Routine abdominal CT with IV contrast is rarely diagnostic and should not be considered for characterization of a known adrenal lesion. FDG-PET/CT Skull Base to Mid-Thigh FDG-PET can be used to identify metastases in oncologic patients in various cancers [26,77-79]. FDG-PET is sensitive to metabolically active lesions, and metastases usually show greater uptake than benign lesions. In several studies, there have been a few false-positives with FDG-PET, lowering specificity to 85% in one study [80], but excellent sensitivity has been achieved [26,77-79]. False-negative scans have occurred in renal cell carcinoma metastases [64]. Adrenal Mass Evaluation SUVs are typically greater for metastatic disease [21]. However, mild activity can be seen in benign adenomas (typically less than background liver), thus potentially leading to false-positive interpretations. Studies have predominantly evaluated FDG-PET or FDG-PET/CT in the oncologic population. However, Tessonnier et al [44] evaluated 41 adrenal tumors in 37 patients who had no history of malignancy using FDG-PET/CT.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. All tumors were without diagnostically benign features on CT or MRI. In this small series, a tumor/liver SUVmax ratio >1.8 yielded 100% sensitivity and specificity for malignancy. 11C-metomidate has been found to localize in adrenocortical tumors and is useful for determining whether a tumor is of adrenocortical origin. However, it cannot distinguish between benign and malignant tumors [64,65]. PET/CT sensitivity to small lesions is diminished and may not detect lesions <1 cm. Image-Guided Biopsy Adrenal Gland In the setting of known primary malignancy, adrenal mass biopsy can be performed when noninvasive tests are inconclusive, when enlarging adrenal masses are seen at follow-up imaging, or to confirm the presence of an adrenal metastasis [81]. If other metastases are present, biopsy may not be necessary. Fine-needle aspiration alone cannot reliably be used to differentiate adrenocortical carcinoma from adrenal adenoma. Also, the sensitivity of needle biopsy for adrenocortical carcinoma is low. In one study, the sensitivity of needle biopsy for detecting adrenocortical carcinoma was reported as 50% [48]. Another study reported the sensitivity as 70% maximally [49]. In addition, percutaneous biopsy of adrenal lesions is not without risk. Complication rates range from 8% to 12% and consist of bleeding, pneumothorax, infection, and anecdotes of tumor seeding of needle tracts. Careful correlation with clinical and endocrinological data is needed, combined with knowledge of other features, such as tumor size and imaging characteristics, to distinguish adenoma from carcinoma due to the possibility of sampling error. Thus, biopsy is better suited to a population with a high risk of malignant lesions and is most useful when noninvasive imaging studies are negative or inconclusive. MRI Abdomen Qualitative and quantitative MRI methods have been used to attempt to distinguish between adenomas and nonadenomas.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. MR-CSI (in-phase and opposed-phase gradient-echo scans), which relies on differentiating lesions whether lesions have fat within tumor cells, with malignant lesions having virtually no fat [50]. This has been shown to be correct for 96% to 100% of cases, depending on the study [51,52]. However, these studies were performed in a mixed population of patients with regard to their history of malignancy, so results may not be directly applicable to populations either with or without known malignancy. As in CT washout characterization, there can be false-positives for adenoma when interpreting CSI with particular metastatic lesions, specifically from clear-cell renal cell carcinoma and hepatocellular carcinoma. Because the diagnosis of adenoma relies on the detection of fat within tumor cells and because hepatocellular carcinoma and renal cell carcinoma primary tumors contain fat in their cells, both hepatocellular carcinoma and renal cell carcinoma adrenal metastases can contain fat and, thus, mimic adenomas [58,82,83]. In cases in which the unenhanced CT attenuation measurement was between 10 and 30 HU (ie, indeterminate by CT), applying CSI can be discriminatory. In one study, 89% of adenomas with densities between 10 and 30 HU were correctly characterized by CSI [59]. Another study concluded that up to 60% of lesions misclassified by Adrenal Mass Evaluation unenhanced CT attenuation measurements can be correctly characterized as adenomas by MR-CSI [53]. Gabriel et al [60] have demonstrated that even heterogeneous loss of signal is evidence of a benign lesion. Thus, MR-CSI may have better sensitivity and specificity than nonenhanced CT. Diffusion-weighted MRI techniques have been investigated in helping to distinguish benign and malignant masses in various organ systems. Neither Miller et al [61] nor Tsushima et al [62] found that this technique could differentiate adrenal adenomas and nonadenomas.


Adrenal Mass Evaluation

Adrenal Mass Evaluation. For the diagnosis of adenoma versus metastasis, contrast- enhanced MRI does not provide additional information beyond the unenhanced technique. However, MRI without and with IV contrast may be considered if there is concern for pheochromocytoma or hypervascular metastasis, as the contrast can show the typical bright enhancement of this lesion. Contrast can also confirm lack of enhancement of a cystic lesion. In patients with a history of malignancy, Candel et al [11] found that 87% of lesions <3 cm were benign and that >95% of lesions >3 cm were malignant. In a similar population, Lee et al [35] found that 79% of lesions <2.5 cm were benign. Van Erkel et al [67] in a mixed population showed that a threshold of 3.1 cm discriminated 93% of lesions. FDG-PET/CT Skull Base to Mid-Thigh FDG-PET can be used to identify metastases in oncologic patients in various cancers [26,77-79]. FDG-PET is sensitive to metabolically active lesions, and metastases usually show greater uptake than benign lesions. In several studies, there have been a few false-positives with FDG-PET, lowering specificity to 85% in one study [80], but excellent sensitivity has been achieved [26,77-79]. False-negative scans have occurred in renal cell carcinoma metastases [64]. SUVs are typically greater for metastatic disease [21]. However, mild activity can be seen in benign adenomas (typically less than background liver), thus potentially leading to false-positive interpretations. Studies have predominantly evaluated FDG-PET or FDG-PET/CT in the oncologic population. However, Tessonnier et al [44] evaluated 41 adrenal tumors in 37 patients who had no history of malignancy using FDG-PET/CT. All tumors were without diagnostically benign features on CT or MRI. In this small series, a tumor/liver SUVmax ratio >1.8 yielded 100% sensitivity and specificity for malignancy. 11C-metomidate has been found to localize in adrenocortical tumors and is useful for determining whether a tumor is of adrenocortical origin.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded .  Typical treatment goals include identification of the causative disease process to facilitate therapy, recovery, and improvement of dyspnea symptoms. Initial diagnostic evaluation is centered about careful history taking and physical examination [1]. Physical examination findings in cardiac causes of dyspnea could include murmurs (eg, systolic murmurs in the setting of valve insufficiency) as well as an abnormality in heart rate or rhythm, extra heart sounds (S3 in setting of ventricular dysfunction, pericardial knock associated with constriction), or jugular vein distention and edema in heart failure. A nuanced accounting of relevant physical examination findings and history is beyond the scope of this document. Diagnostic investigation may be supplemented by chest radiography and electrocardiography (ECG) as well as laboratory testing. However, identifying the cause of dyspnea in some cases remains elusive [7], and advanced diagnostic imaging may play a critical role in the care of these patients. Special Imaging Considerations MRI imaging artifacts in patients with implanted electronic devices [8-11] and arrhythmias [12-14] can be mitigated with use of evolving imaging techniques. Point-of-care scanning with pocket echocardiography has improved time to definitive treatment (83 versus 180 days) and has been associated with improved outcomes, 15% versus 28% hospitalization or death, in a prospective randomized trial involving 253 patients in resource limited areas [15], whereas point-of-care echocardiography scanning with standard equipment obviated the need for formal scans in community patients with asymptomatic murmurs [16], with 100% of abnormalities identified on a point-of-care scan in 175 patients. The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through representation of such organizations on expert panels.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . Participation on the expert panel does not necessarily imply endorsement of the final document by individual contributors or their respective organization. Reprint requests to: publications@acr.org All elements are essential: 1) timing, 2) reconstructions/reformats, and 3) 3-D renderings. Standard CTs with contrast also include timing issues and reconstructions/reformats. Only in CTA, however, is 3-D rendering a required element. This corresponds to the definitions that the CMS has applied to the Current Procedural Terminology codes. OR Discussion of Procedures by Variant Variant 1: Dyspnea due to suspected valvular heart disease. Ischemia excluded. Initial imaging. Arteriography Coronary with Ventriculography There is no relevant literature to support the use of arteriography coronary with ventriculography for the evaluation of dyspnea due to suspected VHD, ischemia excluded. CT Coronary Calcium There is scant literature regarding the use of CT coronary calcium scans in the evaluation of dyspnea due to suspected VHD, ischemia excluded. Presence of mitral annular calcification on CT coronary calcium scans has shown correlation with cardiovascular risk [20]. Coronary artery calcium scanning for the detection and quantification of aortic valve calcium burden may be useful in some instances, for example, in patients with low- gradient aortic stenosis, but is not a first-line imaging examination. CT Heart Function and Morphology CT plays a predominantly supportive role to echocardiography in the assessment of suspected VHD, utilized when echocardiographic images are suboptimal, or to provide complementary information [21]. CT can aid in differentiating aortic leaflet morphologies, with leaflet fusion length, uneven cusp area, and midline calcification all showing strong association with bicuspid valve (P < .


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . 05) [22], with the valve type characterized on surface echocardiography often (20%) reclassified after tomographic imaging with MRI, CT, or transesophageal echocardiography (TEE) [23]. CT may provide additional insight in the setting of suspected mechanical prosthetic valve dysfunction [24] and can also provide precise concomitant anatomic delineation of the entire aorta. CT is increasingly utilized as part of a comprehensive preprocedural preparation for VHD interventions. CT imaging of cardiac and vascular structures plays a critical role in the planning of transcatheter aortic valve Dyspnea-Suspected Cardiac Origin replacement [25], and up to 30.9% and 32.6% of those with suspect clinical and echocardiographic findings posttranscatheter aortic valve replacement or surgical aortic valve repair, respectively [26]. CT imaging is increasingly utilized in planning transcatheter interventions for valvular and structural heart disease beyond the aortic valve [27-29] as well as planning, risk stratification, and follow-up of surgical interventions for VHD [26]. Epicardial fat as assessed on CT has shown correlation with mitral annular and aortic leaflet calcification [30], although this is not routinely employed in clinical practice. CTA Coronary Arteries There is no relevant literature to support the use of CTA coronary arteries for the evaluation of dyspnea due to suspected VHD, ischemia excluded. Coronary ostia heights relative to aortic annulus are assessed on CTA as part of transcatheter aortic valve planning [25]. FDG-PET/CT Heart There is no relevant literature to support the use of fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT heart for the evaluation of dyspnea due to suspected VHD, ischemia excluded. MRI Heart Function and Morphology MRI plays a complementary role to echocardiography in the assessment of suspected VHD.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . MRI may be utilized when echocardiographic images are suboptimal or to provide additional quantitative flow information with use of phase-contrast velocity encoded sequences. MRI offers multiplanar capacity in demonstration of leaflet morphology and motion and is less dependent upon patient anatomy than echocardiography. However, MRI requires multiple cardiac cycles for data collection, and imaging may be compromised in cases of arrhythmia, whereas echocardiography offers real-time valve morphologic assessment and is more mobile. MRI often shows lower peak velocities than Doppler US; however, mean flow is more accurately analyzed with phase-contrast techniques that account for variation in flow across a vessel diameter. MRI may be preferred over echocardiography in the assessment of the pulmonary valve and can be used to grade mitral, pulmonic, or aortic regurgitation if there is clinical uncertainty after echocardiography [21]. The assessment of regurgitant volume, left ventricular (LV) volume, and myocardial fibrosis may play an eventual role in risk prognosis in VHD. MRI quantified aortic insufficiency has shown correlation with surgical repair, with 85% of patients having regurgitant fraction >33% progressing to surgery, typically in <3 years [31]. Discordance between echocardiographic and MRI assessment of mitral insufficiency has been reported (r = 0.6), with MRI predicting postsurgical LV remodeling more accurately (r = 0.85, P < . 0001) than echocardiography (r = 0.32; P = . 1) in a prospective multicenter trial [32]. MRI provides high inter- and intrareader reproducibility [33] with semiautomated flow measurement in the ascending aorta and main pulmonary artery.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . Although CT and echocardiography are most commonly used for planning and follow-up of structural and VHD interventions, MRI is playing an increasing role in this expanding field [35], capitalizing on the good spatial and temporal resolution, large field of view, and inherent tissue characterization available with MRI. Dyspnea-Suspected Cardiac Origin MRI Heart Function with Stress There is no relevant literature to support the use of MRI heart function with stress for the evaluation of dyspnea due to suspected VHD, ischemia excluded. Radiography Chest Chest radiography can provide information on heart failure in the setting of VHD. Diagnosis of specific valve abnormalities is limited, but radiographs may aid in identification of characteristic cardiac chamber and great vessel changes [44] as well as marked calcification of aortic root or mitral annulus. Rb-82 PET/CT Heart There is no relevant literature to support the use of Rb-82 PET/CT heart for the evaluation of dyspnea due to suspected VHD, ischemia excluded. SPECT or SPECT/CT MPI Rest and Stress There is no relevant literature to support the use of single-photon emission computed tomography (SPECT) or SPECT/CT myocardial perfusion imaging (MPI) for the evaluation of dyspnea due to suspected VHD, ischemia excluded. US Echocardiography Transthoracic Resting TTE is the primary modality for diagnosis, assessment, and follow-up of native and prosthetic VHD [21,48], providing insights to anatomy, mechanism of disease, and hemodynamic impact. Evaluation of leaflet morphology is typically obtained first by echocardiography, with proposed schemes to distinguish unicuspid from bicuspid or tricuspid aortic valves [49], although there is reported a common (20%) reclassification of leaflet morphology as determined on surface echocardiography after MRI, CT, or TEE imaging [23], or internal review of echocardiography images [50].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . Bicuspid leaflet morphology as identified on echocardiography can predict valvular function and aortic dilation [51], with a prospective group of 852 patients with bicuspid valve having aortic regurgitation (23%) related to valve prolapse (OR: 5.16, P < . 0001), and aortic stenosis (22%) associated with fused right and noncusps, (OR: 2.09, P < . 001), and the presence of raphe (OR: 2.75, P < 0.001). Gradation of valve abnormality (eg, mild, moderate, or severe aortic stenosis) is predominantly obtained by echocardiography. Echocardiographic assessment of early bioprosthetic valve failure can be addressed systematically with correlation to surgical changes [52]. Patient prosthesis mismatch has been associated with raised transprosthetic pressure after mitral valve replacement, although only when calculated by the continuity equation (P = . 021) [53]. Doppler parameters may be useful in estimating LV filling pressure in patients with mitral annular calcification [54]; in a group of 50 patients with mitral annular calcification, the ratio of early-to-late diastolic filling velocity (mitral E/A) showed the best correlation, (r = 0.66; P < . 001), whereas the ratio of early diastolic filling velocity-to-mitral annulus velocity (E/e') demonstrated weak correlation (r = 0.42; P = . 003). Large-scale screening of populations revealed newly identified VHD in 51% of 2,500 patients >65 years of age, although this was commonly mild [55], with cardiac auscultation by general practitioners showing modest sensitivity and specificity (44% and 69% , respectively) in asymptomatic patients, even in the setting of significant disease [56]. TTE 3-D techniques may improve assessment of mitral or aortic valve dysfunction, with a systematic review showing the strongest evidence for estimating the mitral valve area in patients with rheumatic mitral valve stenosis and the vena contracta area in patients with mitral insufficiency [57].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . Echocardiography has provided mechanistic clarification to tricuspid valve insufficiency induced by device leads; notably, when the lead tip was in the interventricular septum or if the lead was shown to be impinging on a leaflet, the device lead was more likely to impede leaflet mobility (P < . 05), and interfering leads were associated with more significant tricuspid regurgitation than noninterfering leads (P < . 05) [58]. Echocardiographic assessment of the left atrium may improve insights to aortic and mitral valve dysfunction [59]. Dyspnea-Suspected Cardiac Origin Novel strain imaging applications have shown promise in characterizing LV changes in patients with aortic stenosis and aortic insufficiency [60]. Volume loop characteristics (area under receiver operating characteristic curve [AUC] = 0.99, 1.00, and 1.00; all P < . 01) showed improved discrimination relative to peak strain (AUC = 0.75, 0.89, and 0.76; P = . 06, <. 01, and . 08, respectively) and LV ejection fraction (AUC = 0.56, 0.69 and 0.69; all P > . 05) to distinguish aortic valve stenosis versus control, aortic valve regurgitation versus control, and aortic valve stenosis versus aortic valve regurgitation groups, respectively. Strain imaging has also shown promise in providing improved insight to aortopathy and aortic elasticity in patients with a bicuspid valve [61]. US Echocardiography Transthoracic Stress TTE stress may be useful in further characterization of mitral and aortic stenosis, for example, in setting of discrepant resting echocardiographic gradation of stenosis and patient symptoms [21,24], as well as evaluating symptoms and exercise capacity of patients. Stress echocardiography may be useful in determining eligibility for competitive sports [62], with exercise-induced changes to ventricular response and valvular lesion, as well as changes to right ventricular (RV) systolic pressure potentially aiding in decision making.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . Variant 2: Dyspnea due to suspected cardiac arrhythmia. Ischemia excluded. Initial imaging. Arteriography Coronary with Ventriculography There is no relevant literature to support the use of arteriography coronary with ventriculography for the evaluation of dyspnea due to suspected cardiac arrhythmia, ischemia excluded. CT Coronary Calcium There is no relevant literature to support the use of CT coronary calcium for the evaluation of dyspnea due to suspected cardiac arrhythmia, ischemia excluded. CT can provide a precise regional anatomic survey for pre- and intraprocedural guidance of catheter ablation [66], with potential ablation targets notably located within 1 cm of critical structures such as coronary arteries and phrenic nerve in 35 (80%) and 18 (37%) patients, respectively [68]. CT also provides robust anatomic delineation of pulmonary vein and left atrial appendage anatomy [28] for both planning and follow-up of pulmonary vein ablation as well as left atrial appendage occlusion for atrial fibrillation treatment. Measured attenuation of epicardial fat has shown to be a predictor of electrophysiologic properties of the adjacent left atrium in patients with atrial fibrillation [69]. CTA Coronary Arteries There is no relevant literature to support the use of CTA coronary arteries for the evaluation of dyspnea due to suspected cardiac arrhythmia, ischemia excluded. FDG-PET/CT Heart Patients may benefit from PET imaging for scar identification and for prediction of ventricular arrhythmia and sudden cardiac death. Full thickness myocardial scarring has shown strong association with major arrhythmic events after accounting for age, sex, cardiovascular risk factors, beta-blocker therapy, and resting LV ejection fraction Morphologic analysis of fibrotic scarring in nonischemic dilated cardiomyopathy has shown promise in prediction of electrophysiologic impact [77].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . In a group of patients with systemic sclerosis, extracellular volume as measured on MRI corresponded with a risk for significant arrhythmia [78]. In a group of cardiac resynchronization therapy patients, an algorithm based on scar mass as quantitated by MRI identified 148 patients (68.2%) without implantable cardioverter-defibrillator therapy/sudden cardiac death during follow-up with a 100% negative predictive value [79], and appropriate implantable cardioverter-defibrillator therapy can be predicted in ischemic cardiomyopathy patients with primary prevention implantable cardioverter-defibrillator by quantifying the LGE border zone [80]. Concomitant assessment for structural heart disease and LV function can also be obtained. MRI can provide tissue-specific direction for targeted treatment of both ventricular and atrial arrhythmic foci [81,82]. Morphologic and functional criteria as assessed by MRI are useful in cases of suspected ARVC/D [83]. MRI Heart Function with Stress There is no relevant literature to support the use of MRI heart function with stress for the evaluation of dyspnea due to suspected cardiac arrhythmia, ischemia excluded. Radiography Chest There is no relevant literature to support the use of radiography for the evaluation of dyspnea due to suspected arrhythmia, ischemia excluded. Radiography may demonstrate cardiac silhouette enlargement as well as pulmonary vascular cephalization or edema as may be seen in setting of cardiac arrhythmia. Rb-82 PET/CT Heart There is no relevant literature to support the use of Rb-82 PET/CT heart for the evaluation of dyspnea due to suspected cardiac arrhythmia, ischemia excluded. SPECT or SPECT/CT MPI Rest and Stress There is scant literature regarding the use of SPECT or SPECT/CT MPI in the assessment of suspected arrhythmia.


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . MPI can elucidate remodeling in patients who are postcardiac resynchronization therapy, with differential incidence of ventricular arrhythmia [84], and gated SPECT imaging phase analysis has shown potential in differentiating degrees of mechanical dyssynchrony [85]. Dyspnea-Suspected Cardiac Origin US Echocardiography Transesophageal There is scant literature regarding the use of TEE in the assessment of suspected arrhythmia. Left atrial appendage size (left atrial appendage end-diastolic volume [P = . 002; OR 1.6] and morphology [cauliflower shape (P = . 001; OR, 10.2)]) are predictive of thromboembolic events in patients with nonvalvular atrial fibrillation [86]. US Echocardiography Transthoracic Resting Echocardiography is an important noninvasive imaging technique in the diagnosis and prognosis of patients with arrhythmias, providing insight into associated myocardial, valvular, and structural disorders. Morphologic and functional criteria are useful in RV assessment in cases of suspected ARVC/D [83]. Assessment of LV function by speckle-tracking strain assessment has shown utility in prediction of ventricular arrhythmia in patients post-LV assist devices placement [87], and ejection fraction as assessed by echocardiography has shown predictive value in ventricular arrhythmia as well as in all-cause mortality in heart failure patients with implantable cardioverter- defibrillators [88]. Although epicardial fat is rarely noted on clinical reports, associations have been noted between epicardial fat thickness as measured on echocardiography and dysrhythmia [94], in the prediction of successful electrical cardioversion and atrial fibrillation recurrence [95,96], and in the ablation of premature ventricular contractions [97]. Measurement of left atrial volume has shown to be a predictor of persistent atrial fibrillation after mitral valve surgery, with indexed volume >39 mL/m2 having a sensitivity of 79% (AUC: 0.762, SE: 0.051, P < . 001) [98].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . US Echocardiography Transthoracic Stress There is no relevant literature to support the use of TTE stress for the evaluation of dyspnea due to suspected arrhythmia, ischemia excluded. Variant 3: Dyspnea due to suspected pericardial disease. Ischemia excluded. Initial imaging. Arteriography Coronary with Ventriculography There is no relevant literature to support the use of arteriography coronary with ventriculography for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. This is distinguished from right heart catheterization. CT Chest Without and With IV Contrast There is no relevant literature to support the use of CT chest without and with IV contrast for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. CT Chest With IV Contrast There is no relevant literature to support the use of CT chest with IV contrast for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. Although this procedure is not a first-line imaging test, it may provide information on pericardial changes such as effusion, thickening, or enhancement. Dyspnea-Suspected Cardiac Origin CT Coronary Calcium There is no relevant literature to support the use of CT coronary calcium for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. CT Heart Function and Morphology CT is useful in depiction of abnormal pericardial thickening as well as in defining the extent of pericardial calcification [100]. CT can be considered for assessing size, location, and density of pericardial effusion, which may not be fully demonstrated by echocardiography, and can be used for planning before pericardiocentesis or pericardial cardiectomy. In cases of suspected pericardial masses or tumors, CT can be used for assessment of size and location, involvement or invasion of adjacent structures, and extracardiac findings such as lymphadenopathy [101].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . CT provides limited and indirect hemodynamic information, such as enlargement of the atria and venae cavae in cases of pericardial constriction. Functional evaluation using CT is possible using retrospective ECG-gated examination, although the utility of such techniques are challenged by breath-held acquisition, suboptimal temporal resolution compared to echocardiography, and MRI as well as the potential increased artifact case of tachycardia or unstable heart rhythm [100,102]. Epicardial fat volume quantitation by CT has shown some association with the outcome of patients with a first episode of acute pericarditis and a potential prognostic implication [103], although this has limited clinical application to date. CTA Chest There is no relevant literature to support the use of CTA chest for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. Although this procedure is not a first-line imaging test, it may provide information on pericardial changes such as effusion, thickening, or enhancement. CTA Coronary Arteries There is no relevant literature to support the use of CTA coronary arteries for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. FDG-PET/CT Heart There is limited literature regarding the use of FDG-PET/CT in the assessment of suspected pericardial disease, ischemia excluded. The presence of pericardial inflammation as stratified by standardized uptake values can predict reversibility of transient constrictive pericarditis with medical treatment. Using pericardial maximized standardized uptake value of 3.0 as a cutoff value, sensitivity, specificity, positive predictive value, and negative predictive value of FDG-PET/CT for predicting response to medical treatment were 100%, 71%, 82%, and 100%, respectively, in a small group (n = 16) of prospectively recruited patients with constrictive pericarditis [104].


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . FDG-PET/CT may be helpful in making a presumptive diagnosis of malignancy, especially in nondiagnostic pericardial effusion with relatively high-risk pericardiocentesis, or may guide selection of an optimal biopsy site with a potential high yield of disease. However, infectious processes such as tuberculosis can show increased FDG uptake mimicking malignancy, which limits FDG-PET/CT utility in differentiation between benign and malignant pericardial disease [105]. MRI Heart Function and Morphology MRI is typically an adjuvant test when echocardiographic data are ambiguous or inconclusive for constriction [102]. MRI can provide reliable depiction of pericardial thickening, typically with dark blood imaging, with prognostic value for patients eventually progressing to surgical resection. Furthermore, cardiac MR, real-time cine imaging with free breathing can suggest constrictive pathophysiology where the septum shifts toward the left ventricle during early inspiration. A model combining pericardial thickness and relative interventricular septal excursion provided the best overall performance in prediction of constrictive pericarditis in a surgical series of patients (C statistic, 0.98, 100% sensitivity, 90% specificity) [106], although shallow breaths or vigorous inspiration may result in false negative or false positive results, respectively [107]. LGE can reveal the presence and severity of pericardial inflammation [102], with histologic changes corresponding to MRI appearance. MRI may define the extent of associated myocarditis when there is a concern of myocardial involvement and echocardiography is inconclusive [107]. MRI can provide incremental value to evaluate the presence and severity of active pericardial inflammation in patients with constrictive pericarditis [107]. Pericardial delayed hyperenhancement quantitative assessment on cardiac MRI can be a helpful prognostic tool in the care of


Dyspnea Suspected Cardiac Origin Ischemia Already Excluded . MRI is useful for assessing pericardial masses and tumors, particularly for accurate localization and sizing and tissue characterization [101,110], and to delineate potential extension to adjacent thoracic anatomic structures. MRI Heart Function with Stress There is no relevant literature to support the use of MRI heart function with stress for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. Radiography Chest Chest radiograph may show suggestive findings of pericardial effusion, pericardial calcifications, pericardial cyst, and pericardial defect/absence, although this generally has a lower diagnostic potential to delineate pericardial abnormities compared with echocardiography, CT, and MRI. Rb-82 PET/CT Heart There is no relevant literature to support the use of Rb-82 PET/CT heart for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. SPECT or SPECT/CT MPI Rest and Stress There is no relevant literature to support the use of SPECT or SPECT/CT MPI rest and stress for the evaluation of dyspnea due to suspected pericardial disease, ischemia excluded. US Echocardiography Transesophageal TEE can be considered in assessing pericardial disease in a patients with suspected complicated acute pericarditis, constrictive pericarditis, or pericardial masses if TTE images are of poor quality [102]. US Echocardiography Transthoracic Resting TTE is safe and typically considered the first-line imaging modality in almost all types of pericardial diseases [100,102]. Most acute pericarditis cases are uncomplicated, and echocardiography is the first and only imaging test necessary, with diagnosis based on characteristic chest pain and ECG changes. Echocardiography is performed primarily for risk stratification and may identify a pericardial effusion, evidence of pericardial tamponade, wall motion abnormalities, or features of pericardial constriction [102].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma.  Recent advances in the molecular cytogenetics of RCC have significantly enhanced understanding of the pathogenesis, tumor biology, management, and prognosis of this highly heterogeneous malignancy. In 2016, the World Health Organization published the revised classification of renal tumors. There are more than 14 histological subtypes of RCC, but the majority of RCC belong to 3 histological variants, namely clear-cell RCC (75%), papillary RCC (10%-15%), and chromophobe RCC (4%-6%) [3]. Tumor stage is an extremely important prognostic factor in RCC. Patients with stage I localized RCC have an 81% 5-year survival rate compared with just an 8% 5-year survival rate for those with stage IV RCC. Staging of RCC is performed using the TNM staging system, which was developed by the American Joint Committee on Cancer (AJCC) [4]. aThe University of Texas MD Anderson Cancer Center, Houston, Texas. bPanel Chair, UT Southwestern Medical Center, Dallas, Texas. cThe University of Texas MD Anderson Cancer Center, Houston, Texas, Primary care physician. dFeinberg School of Medicine, Northwestern University, Chicago, Illinois; Commission on Nuclear Medicine and Molecular Imaging. eMayo Clinic, Jacksonville, Florida. fUniversity of British Columbia, Vancouver, British Columbia, Canada. gThe University of Texas MD Anderson Cancer Center, Houston, Texas. hDuke University Medical Center, Durham, North Carolina. iThomas Jefferson University Hospital, Philadelphia, Pennsylvania. jMallinckrodt Institute of Radiology Washington University School of Medicine, Saint Louis, Missouri; Commission on Radiation Oncology. kSUNY Upstate Medical University, Syracuse, New York. lPresbyterian Medical Center, University of Pennsylvania, Philadelphia, Pennsylvania; American Urological Association. mCleveland Clinic, Cleveland, Ohio. nUniversity of Alabama at Birmingham, Birmingham, Alabama. oNew York University Langone Medical Center, New York, New York. pSpecialty Chair, Northwestern University, Chicago, Illinois.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through representation of such organizations on expert panels. Participation on the expert panel does not necessarily imply endorsement of the final document by individual contributors or their respective organization. Reprint requests to: publications@acr.org Staging of Renal Cell Carcinoma presence of any nodal metastases (N1) and/ or T3 tumor. Stage IV disease is the presence of any distant metastases (M1) and/or presence of T4 tumor. Curative treatment for RCC may be accomplished with surgical resection. Partial nephrectomy is the preferred treatment option for small T1 RCC, especially because it is associated with lower risk of renal failure and cardiovascular mortality compared to radical nephrectomy. However, it has been reported that incidence of complications such as postoperative bleeding and urinary leaks may be high in partial nephrectomy. Hence, urologists carefully select patients for partial nephrectomy using preoperative scoring systems, such as the Preoperative Aspects and Dimensions Used for Anatomic assessment score, Renal Nephrometry Score, and Centrality Index. Although a full description of these scoring systems is beyond the scope of this manuscript, urologists consider various factors for surgical planning including size of the tumor and the number of lesions (such as presence of multiple and/or bilateral tumors). The location of the tumor is another important criteria. Factors such as tumor location in the upper/mid/lower pole of the kidney, tumor location in the anterior versus posterior renal cortex, location in the medial or lateral rim, and presence of exophytic versus endophytic tumor may impact the decision to perform partial nephrectomy.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. Furthermore, tumor involvement of renal sinus and perinephric fat, involvement of renal vein and IVC, tumor extension into adjacent organs, and presence of nodal and distant metastases are critical information needed for treatment planning. Although partial nephrectomy may be the preferred curative option in many patients, active surveillance and local ablative therapies are being increasingly considered in carefully selected patients in the management of small localized T1 RCC [5]. Locally advanced T2 to T4 RCC and complex tumors not amenable for partial nephrectomy approach may benefit from radical nephrectomy. Metastatic disease at presentation varies with the patient series but typically occurs in approximately 1 in 10 patients [6,7]. The most common sites of distant metastases, in descending order, are the lungs, bone, retroperitoneal and mediastinal nodes, liver, brain, or multiple sites [8,9]. Radical nephrectomy with metastasectomy remains an option for carefully selected patients with oligo-metastases. Similarly, cytoreductive nephrectomy may be considered even in advanced stage RCC. However, many patients with advanced stage RCC present with multifocal metastatic disease, warranting a multidisciplinary approach. Better understanding of RCC tumor biology has paved the way for the development of numerous FDA-approved therapeutic options for advanced stage RCC including targeted therapy and immunotherapy. Imaging plays an important role in the staging of RCC [10]. In this document, we provide an update on the appropriate use of imaging examinations for initial staging of known RCC. Special Imaging Considerations CT urography (CTU) is an imaging study that is tailored to improve visualization of both the upper and lower urinary tracts.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. There is variability in the specific parameters, but it usually involves unenhanced images followed by intravenous (IV) contrast-enhanced images, including nephrographic and excretory phases acquired at least 5 minutes after contrast injection. Alternatively, a split-bolus technique uses an initial loading dose of IV contrast and then obtains a combined nephrographic-excretory phase after a second IV contrast dose; some sites include arterial phase. CTU should use thin-slice acquisition. Reconstruction methods commonly include maximum intensity projection or 3-D volume rendering. For the purposes of this document, we make a distinction between CTU and CT abdomen and pelvis without and with IV contrast. CT abdomen and pelvis without and with IV contrast is defined as any protocol not specifically tailored for evaluation of the upper and lower urinary tracts and without both the precontrast and excretory phases. MR urography (MRU) is also tailored to improve imaging of the urinary system. Unenhanced MRU relies upon heavily T2-weighted imaging of the intrinsic high signal intensity from urine for evaluation of the urinary tract. IV contrast is administered to provide additional information regarding obstruction, urothelial thickening, focal lesions, and stones. A contrast-enhanced T1-weighted series should include corticomedullary, nephrographic, and excretory phases. Thin-slice acquisition and multiplanar imaging should be obtained. For the purposes of this document, we make a distinction between MRU and MRI abdomen and pelvis without and with IV contrast. MRI abdomen and pelvis without and with IV contrast is defined as any protocol not specifically tailored for evaluation of the upper and lower urinary tracts, without both the precontrast and excretory phases, and without heavily T2-weighted images of the urinary tract. Staging of Renal Cell Carcinoma Discussion of Procedures by Variant Variant 1: Renal cell carcinoma.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. No contraindication to either iodinated CT contrast or gadolinium-based MR intravenous contrast. Staging. Bone Scan Whole Body The prevalence of osseous metastases for localized RCC has been shown to be low in patients without symptoms (ie, bone pain) or without laboratory abnormalities suggestive of osseous metastases (ie, elevated serum alkaline phosphatase level) [11,12]. Furthermore, the sites commonly involved by osseous metastases, such as the thoracolumbar spine and ribs, are located in areas covered by chest and abdominal imaging. Thus, even though bone scanning can be helpful to confirm clinically or radiographically suspected metastatic disease, current guidelines from the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) do not support its routine use in the initial staging of asymptomatic RCC [5,13]. However, in patients with RCC with symptoms suspicious for bone metastases, bone scan may be useful. Bone Scan Whole Body with SPECT or SPECT/CT Area of Interest The prevalence of osseous metastases for localized RCC has been shown to be low in patients without symptoms (ie, bone pain) or without laboratory abnormalities suggestive of osseous metastases (ie, elevated serum alkaline phosphatase level) [11,12]. Furthermore, the sites commonly involved by osseous metastases, such as the thoracolumbar spine and ribs, are located in areas covered by chest and abdominal imaging. Thus, even though bone scanning can be helpful to confirm clinically or radiographically suspected metastatic disease, current guidelines do not support its routine use in the initial staging of asymptomatic RCC [5,13]. In patients with RCC with symptoms suspicious for bone metastases, bone scan may be useful.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. If the bone scan shows areas of abnormal radiotracer uptake suspicious for osseous metastases, single-photon emission CT (SPECT) fused with CT can be used to provide detailed anatomic localization of the abnormal radiotracer uptake and further improve the characterization of the nature of the abnormality [14]. CT Abdomen Preoperative imaging of RCC provides critical information on staging and serves as a roadmap to the surgeon. Both CT and MRI are comparable in staging of the primary tumor [15,16]. CT of the abdomen with IV contrast is considered in all major guidelines as an adequate method for staging of RCC, including the guidelines from the EAU and NCCN [5,13]. Use of IV contrast helps in the diagnosis and staging of the RCC [14,15,17-27]. Acquisition of nephrographic phase images is vital and most important in the detection and characterization of RCC. Corticomedullary phase images and excretory phase images are optional and may be helpful in differentiating RCC subtypes, distinguishing RCC from urothelial tumors and in providing complementary information on the vasculature and tumor extension into pelvicalyceal system. Extension into the perinephric fat is difficult to discriminate from nonspecific perinephric stranding due to edema, vascular engorgement, or fibrosis. High-resolution CT using thin sections appears to improve detection of perinephric infiltration, although false positives are common [15,16,33]. Various authors have reported 85% to 93% sensitivity and 32% to 96% specificity for the detection of perinephric invasion on IV contrast-enhanced CT abdomen [33-35]. In a study involving 117 patients, CT abdomen was reported to have a sensitivity of 59% to 88% and a specificity of 71% to 93% in detecting stage T3a RCC [36].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. In particular, CT had a 71% to 88% sensitivity and 71% to 79% specificity for renal sinus fat invasion, a 68% to 83% sensitivity and a 72% to 76% specificity for perinephric fat invasion, and a 59% to 69% sensitivity and a 91% to 93% specificity for renal vein invasion [36]. In a more recent study, 96 patients with 100 pathologically proven RCC, CT was reported to have an 86% sensitivity and 88% specificity for renal sinus fat invasion and an approximately 86% sensitivity and 97% specificity for renal vein invasion [37]. However, CT only had a modest 77% sensitivity and 72% specificity for detecting perinephric fat invasion in this study, emphasizing the difficulties in differentiating nontumoral causes for perinephric soft tissue stranding, from true tumor perinephric fat invasion [37]. Staging of Renal Cell Carcinoma It has been reported that the presence of enhancing soft tissue nodule in the perinephric fat on CT may be a helpful sign for the assessment of perinephric fat invasion. Landman et al [38] reported that the presence of enhancing perinephric soft tissue nodule had an 87% accuracy in predicting perinephric fat invasion compared with the CT finding of perinephric soft tissue stranding, which only had a 56% accuracy. However, the sensitivity of enhancing perinephric soft tissue nodule in detection of perinephric fat invasion is relatively low (31%) [38]. CT has an excellent sensitivity for detecting ipsilateral adrenal involvement in RCC (T4 tumors), but the specificity varies from 76% to 95%. One study involving 229 patients with RCC reported that CT had a 100% sensitivity for ipsilateral adrenal involvement in RCC, but only a 76% specificity [39]. However, Blakely et al [40] reported a 100% sensitivity and a 94% specificity for CT in identifying adrenal involvement. Similar findings have been reported by other authors.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. In another study involving 579 patients, CT was reported to have a 100% negative predictive value, a 100% sensitivity, and a 95% specificity for identifying adrenal involvement [41]. Assessment of RCC nodal metastases on CT is limited [42]. This is due to the fact that CT uses size criteria for nodal metastasis (size >1 cm in short-axis), but this leads to underestimation of disease, resulting in false negatives in the presence of micrometastases in nodes <1 cm in size. Furthermore, false positives are also often seen because of presence of reactive adenopathy, with nodes >1 cm in size. CT is accurate in detecting distant metastases in the abdomen. RCC visceral metastases may occur at various organs including liver, pancreas, adrenals, and contralateral kidney. RCC metastases tend to be hypervascular, and some authors have suggested that arterial phase imaging can be useful to accurately detect the extent of distant metastases [43-46]. CT Abdomen and Pelvis Preoperative imaging of RCC provides critical information on staging and serves as a roadmap to the surgeon. Both CT and MRI are comparable in staging of the primary tumor [15,16]. Advantages of CT include rapid acquisition time that may translate to better patient compliance and high spatial resolution. Hence, it is often the most commonly used modality for this indication. CT abdomen without and with IV contrast is typically performed for charactering a renal mass as RCC and staging the tumor. Acquisition of nephrographic phase images is vital and most important in the detection and characterization of RCC. Corticomedullary phase images and excretory phase images are optional and may be helpful in differentiating RCC subtypes, distinguishing RCC from urothelial tumors and in providing complementary information on the vasculature and tumor extension into pelvicalyceal system. Perinephric tumor extension is difficult to discriminate from nonspecific perinephric stranding due to edema, vascular engorgement, or fibrosis.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. High-resolution CT using thin sections appears to improve detection of perinephric infiltration, although false positives are common [15,16,33]. Various authors have reported an 85% to 93% sensitivity and a 32% to 96% specificity for perinephric invasion [33-35]. In a study involving 117 patients, CT abdomen was reported to have a sensitivity of 59% to 88% and a specificity of 71% to 93% in detecting stage T3a RCC [36]. In particular, CT had a 71% to 88% sensitivity and a 71% to 79% specificity for sinus fat invasion, a 68% to 83% sensitivity and a 72% to 76% specificity for perinephric invasion, and a 59% to 69% sensitivity and a 91% to 93% specificity for renal vein invasion [36]. In a more recent study of 96 patients with 100 pathologically proven RCCs, CT was reported to have an 86% sensitivity and an 88% specificity for renal sinus invasion and an approximately 86% sensitivity and a 97% specificity for renal vein invasion [37]. However, CT only had a modest 77% sensitivity and 72% specificity for detecting perinephric invasion in this study, emphasizing the difficulties in differentiating nontumoral causes for perinephric soft tissue stranding from true tumor perinephric infiltration [37]. It has been reported that presence of enhancing soft tissue nodule in the perinephric fat on CT may be a helpful sign for assessment of perinephric fat invasion. Landman et al [38] reported that the presence of enhancing perinephric soft tissue nodule had an 87% accuracy in predicting perinephric fat invasion compared with the CT finding of perinephric soft tissue stranding, which only had a 56% accuracy. However, the sensitivity of enhancing perinephric soft tissue nodule in detection of perinephric invasion is relatively low (31%) [38]. Staging of Renal Cell Carcinoma CT has excellent sensitivity for detecting ipsilateral adrenal involvement in RCC (T4 tumors), but the specificity varies from 76% to 95%.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. One study involving 229 patients with RCC reported that CT had a 100% sensitivity for ipsilateral adrenal involvement in RCC but only a 76% specificity [39]. However, Blakely et al [40] reported a 100% sensitivity and a 94% specificity for CT in identifying adrenal involvement. Similar findings have been reported by other authors. In another study involving 579 patients, CT was reported to have a 100% negative predictive value, a 100% sensitivity, and a 95% specificity for identifying adrenal involvement [41]. Assessment of RCC nodal metastases on CT is limited [42]. This is due to the fact that CT uses size criteria for nodal metastasis (size >1 cm in short-axis), but this leads to underestimation of disease, resulting in false negatives in the presence of micrometastases in nodes <1 cm in size. Furthermore, false positives are also often seen because of the presence of reactive adenopathy, with nodes >1 cm in size. CT is fairly accurate in detecting distant metastases in the abdomen and pelvis. RCC visceral metastases may occur at various organs including liver, pancreas, adrenals, and contralateral kidney. RCC metastases tend to be hypervascular, and some authors have suggested that arterial phase imaging can be useful to accurately detect the extent of distant metastases [43-46]. Although CT of the abdomen with IV contrast is considered in all major guidelines as an adequate method for the staging of RCC, imaging of the pelvis for RCC staging is considered optional in the guidelines [5,13]. There is no relevant literature with high-quality evidence regarding the use of CT of the pelvis in the staging of RCC. Although it is likely that CT pelvis may not offer additional information in most patients with early stage RCC, pelvic imaging can be helpful in patients with more advanced RCC, in whom metastatic spread is suspected [47,48]. CT Chest Chest imaging is indicated in the staging of RCC, given that lungs are one of the most common sites of metastases in RCC [5,13].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. There is a lack of literature that have directly compared the accuracy of chest CT with chest radiography for detecting pulmonary metastases in the initial staging of RCC. However, limited data have demonstrated that CT is more sensitive than radiography for the detection of pulmonary metastases from RCC [49]. Hence, CT chest with IV contrast is recommended by the current NCCN guidelines [13]. Apart from identifying pulmonary metastases, chest CT has a high sensitivity for the detection of hilar and mediastinal nodal metastases from RCC [50]. Although it is generally accepted that CT has a high sensitivity for detecting pulmonary nodules, it should be noted that presence of small subcentimeter pulmonary nodules does not equate to pulmonary metastases. Most patients with small T1a RCCs are unlikely to have pulmonary metastases. Prior studies have reported that the risk of metastases is highly correlated with size of the tumor and is virtually nonexistent in tumors <2 cm in size, occurs <1% in tumors of 2 to 3 cm, and occurs approximately 1% to 2% for lesions 3 to 4 cm [51-53]. Hence, the presence of small subcentimeter pulmonary nodules in T1a RCCs is often likely to be a false-positive finding (ie, intrapulmonary lymph nodes and granulomas) but can lead to further unnecessary and potentially invasive investigations. CT Head Most patients with metastases to the central nervous system are symptomatic. Thus, current guidelines from the EAU and NCCN do not support routine imaging of the brain to search for metastases in asymptomatic patients in the initial staging of RCC. Brain imaging should be performed only in cases with suggestive signs or symptoms [5,13]. Recent studies indicate that up to 4% of patients with advanced, metastatic RCC may harbor asymptomatic brain metastasis [56,57]. Hence, routine brain imaging with IV contrast may be considered in patients with advanced, metastatic RCC, even if they are asymptomatic [56,57].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. Staging of Renal Cell Carcinoma CTU There is no relevant literature suggesting that CTU offers any additional benefit over conventional CT of the abdomen in the initial staging of RCC, and thus, this method is not included in the guidelines from the EAU and NCCN [5,13]. FDG-PET/CT Skull Base to Mid-Thigh Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT has a limited role in the diagnosis and local staging of RCC [58]. Differentiating renal tumor from background normal renal tissue can be difficult because of the renal excretion of FDG. Furthermore, RCC is reported to have variable FDG avidity, limiting its utility. Nakanishi et al [59] reported a 56% sensitivity, a 67% specificity, a 15% positive predictive value, a 57% negative predictive value, and a 65% accuracy for FDG-PET in the staging of RCC. A recent clinical trial from Turkey involving 62 patients with RCC reported an 84% accuracy for contrast-enhanced FDG-PET/CT in staging RCC [60]. However, further studies are warranted before PET/CT can be used in the routine initial staging of RCC. At present, given the paucity of literature to support the use of FDG-PET/CT, the guidelines from the EAU and NCCN do not recommend routine FDG-PET/CT in the initial staging of RCC [5,13]. Fluoride PET/CT Skull Base to Mid-Thigh Preliminary results for other PET tracers are also becoming available. In a small prospective study of 10 patients with metastatic RCC, 18F-sodium fluoride (NaF) PET/CT was found to be significantly more sensitive for the detection of RCC skeletal metastases than Tc-99m bone scintigraphy or CT, with sensitivities of 100%, 29%, and 46%, respectively. CT and Tc-99m bone scintigraphy in this study identified only 65% of the metastases detected by fluoride PET/CT [61].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. However, given the paucity of litereature for utility of fluoride PET/CT in the initial staging of RCC, current guidelines from the EAU and NCCN do not support routine fluoride PET/CT to search for metastases in asymptomatic patients in the initial staging of RCC [5,13]. MRI Abdomen and Pelvis MRI of the abdomen without and with IV contrast is considered a reliable method for the staging of RCC. Various MR sequences, including T2-weighted, chemical shift T1-weighted, contrast-enhanced T1-weighted, and diffusion- weighted images, are typically obtained for the staging of RCC. In a study involving 40 patients with RCC, MRI was reported to have an accuracy of 81% to 86% for T staging [62]. Breath-hold MRI showing a lack of perinephric fat involvement is reported to have a high negative predictive value for no perinephric tumor invasion [63]. In a study of 73 RCCs, Roy et al [64] showed that the presence of a pseudocapsule on MRI had an accuracy of 93% for clear-cell carcinomas in separating T1/T2 tumors from T3a tumors. Lal et al [65] performed a prospective observational study in 50 patients with RCC, comparing MRI with histopathological findings. In this study, MRI was reported to have a 90% agreement with histopathology for detecting perirenal extension and a 97% agreement with histopathology for detecting tumor extension beyond Gerota fascia [65]. Both contrast-enhanced multidetector CT and MRI are helpful in detecting venous involvement, particularly in the main renal vein and the IVC [33,66]. Increased diameter of the IVC and renal vein, presence of tumor signal both inside and outside the vessel wall, altered signal intensity in the vessel wall, presence of flow around the tumor thrombus, and mobility in different phases are some of the MRI features that are helpful in detecting venous involvement [67,68].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. Bland thrombus featuring a uniform signal intensity and lack of enhancement after gadolinium can be distinguished from tumor thrombus, which exhibits intermediate or high signal intensity, heterogeneous intensity, and, more reliably, the presence of small vessels. In a recent study involving 81 patients with RCC, MRI was reported to have a 92% sensitivity, an 86% specificity, an 89% positive predictive value, and a 91% negative predictive value for identifying IVC wall invasion [69]. Pitfalls of MRI include the potential for large tumors to compress the vena cava and cause flow-related artifacts. Such artifacts can be reduced with appropriate saturation pulses. Although MRI of the abdomen with IV contrast is considered in all major guidelines as an adequate method for the staging of RCC, imaging the pelvis for RCC staging is considered optional in the guidelines [5,13]. There is no relevant literature with high-quality evidence regarding the use of MRI of the pelvis in the staging of RCC. Although it is likely that MRI pelvis may not offer additional information in most patients with early stage RCC, pelvic imaging can be helpful in patients with more advanced RCC, in whom metastatic spread is suspected [47,48]. MRI Abdomen MRI of the abdomen without and with IV contrast is considered to be a reliable method for the staging of RCC. Various MR sequences, including T2-weighted, chemical shift T1-weighted, contrast-enhanced T1-weighted, and diffusion-weighted images, are typically obtained for the staging of RCC. In a study involving 40 patients with Staging of Renal Cell Carcinoma RCC, MRI was reported to have an accuracy of 81% to 86% for T staging [62]. Breath-hold MRI showing a lack of perinephric fat involvement is reported to have a high negative predictive value for no perinephric tumor invasion [63].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. In a study of 73 RCCs, Roy et al [64] showed that the presence of a pseudocapsule on MRI had an accuracy of 93% for clear-cell carcinomas in separating T1/T2 tumors from T3a tumors. Lal et al [65] performed a prospective observational study in 50 patients with RCC, comparing MRI with histopathological findings. In this study, MRI was reported to have a 90% agreement with histopathology for detecting perirenal extension and a 97% agreement with histopathology for detecting tumor extension beyond Gerota fascia [65]. Both contrast-enhanced multidetector CT and MRI are helpful in detecting venous involvement, particularly in the main renal vein and the IVC [33,66]. Increased diameter of the IVC and renal vein, presence of tumor signal both inside and outside the vessel wall, altered signal intensity in the vessel wall, presence of flow around the tumor thrombus, and mobility in different phases are some of the MRI features that are helpful in detecting venous involvement [67,68]. Bland thrombus featuring a uniform signal intensity and lack of enhancement after gadolinium can be distinguished from tumor thrombus, which exhibits intermediate or high signal intensity, heterogeneous intensity, and, more reliably, the presence of small vessels. In a recent study involving 81 patients with RCC, MRI was reported to have a 92% sensitivity, an 86% specificity, an 89% positive predictive value, and a 91% negative predictive value for identifying IVC wall invasion [69]. Pitfalls of MRI include the potential for large tumors to compress the vena cava and cause flow-related artifacts. Such artifacts can be reduced with appropriate saturation pulses. MRI Head Most patients with metastases to the central nervous system are symptomatic. Thus, current guidelines do not support routine imaging of the brain to search for metastases in asymptomatic patients in the initial staging of RCC. Brain imaging with contrast should be performed only in cases with suggestive signs or symptoms [5,13].


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. Recent studies indicate that up to 4% of patients with advanced, metastatic RCC may harbor asymptomatic brain metastasis [56,57]. Hence, routine brain imaging with IV contrast may be considered in patients with advanced, metastatic RCC, even if they are asymptomatic [56,57]. MRU There is no relevant literature suggesting that MRU offers any additional benefit over conventional MRI of the abdomen in the initial staging of RCC, and thus, this method is not included in the guidelines from the EAU and NCCN [5,13]. Radiography Chest The lung is the most common site of metastases in patients with RCC presenting with synchronous metastases. Although the incidence of metastases in RCC <4 cm is low (approximately 1%-2%), it has been reported that 20% to 30% of T1a tumors may have potentially aggressive histologic features. Hence, chest radiography is usually performed in the staging of RCC [13]. However, CT is more sensitive than radiography for the detection of pulmonary metastases from RCC during staging. In addition to a high sensitivity for the detection of pulmonary metastases, chest CT has a high sensitivity for the detection of intrathoracic nodal metastases from RCC. Therefore, in patients with higher risk of pulmonary metastases (such as tumor >4 cm, cN1, presence of systemic symptoms), chest CT is preferred [54,55]. US Abdomen Ultrasound (US) can be useful in the characterization of renal masses because it can help in differentiating solid and cystic renal masses. However, it is seldom used in the staging of RCC because of its relatively poor performance in evaluating local tumor spread and metastatic disease [70,71]. US can be challenging to perform in patients with a high body mass index. Additional challenges in the use of US may be related to incomplete visualization of the mass, acoustic shadowing from partially calcified cysts or masses, variability in echogenicity of hemorrhagic cysts, and poor sensitivity in diagnosing isoechoic small renal tumors.


Staging of Renal Cell Carcinoma

Staging of Renal Cell Carcinoma. There is no relevant literature suggesting that US offers any additional benefit over conventional CT or MRI of the abdomen in the initial staging of RCC, and thus, this method is not included in the guidelines from the EAU and NCCN [5,13]. However, intraoperative US may be helpful in performing partial nephrectomy, especially in patients with endophytic renal tumors [72,73]. Staging of Renal Cell Carcinoma Variant 2: Renal cell carcinoma. Contraindication to both iodinated CT and gadolinium-based MR intravenous contrast. Staging. Bone Scan Whole Body The prevalence of osseous metastases for localized RCC has been shown to be low in patients without symptoms (ie, bone pain) or without laboratory abnormalities suggestive of osseous metastases (ie, elevated serum alkaline phosphatase level) [11,12]. Furthermore, the sites commonly involved by osseous metastases, such as the thoracolumbar spine and ribs, are located in areas covered by chest and abdominal imaging. Thus, even though bone scanning can be helpful to confirm clinically or radiographically suspected metastatic disease, current guidelines do not support its routine use in the initial staging of asymptomatic RCC [5,13]. Bone Scan Whole Body with SPECT or SPECT/CT Area of Interest The prevalence of osseous metastases for localized RCC has been shown to be low in patients without symptoms (ie, bone pain) or without laboratory abnormalities suggestive of osseous metastases (ie, elevated serum alkaline phosphatase level) [11,12]. Furthermore, the sites commonly involved by osseous metastases, such as the thoracolumbar spine and ribs, are located in areas covered by chest and abdominal imaging. Thus, even though bone scanning can be helpful to confirm clinically or radiographically suspected metastatic disease, current guidelines do not support its routine use in the initial staging of asymptomatic RCC [5,13]. In patients with RCC with symptoms suspicious for bone metastases, bone scan may be useful.