STATE-OF-THE-ART REVIEW IN ENDOCRINOLOGY
Von L * SINCE 1925*
Role of radiologists in the diagnosis and management of adrenal disorders
Sota Oguro1) (D, Hiromitsu Tannai1) (D, Hideki Ota1) (D, Kazumasa Seiji2) (D, Hiroki Kamada1),
Yoshitaka Toyama1) (D, Kei Omata3),4), Yuta Tezuka3),4) (D, Yoshikiyo Ono3),4) (D, Fumitoshi Satoh4) (D,
Sadayoshi Ito5) (D, Tetsuhiro Tanaka4), Hideki Katagiri3) and Kei Takase1) (D
1) Department of Diagnostic Radiology, Tohoku University Hospital, Miyagi 980-8574, Japan
2) Department of Diagnostic Radiology, South Miyagi Medical Center, Miyagi 989-1253, Japan
3) Department of Diabetes, Metabolism and Endocrinology, Tohoku University Hospital, Miyagi 980-8574, Japan
4) Division of Nephrology, Rheumatology and Endocrinology, Tohoku University, Miyagi 980-8574, Japan
5) Department of Nephrology, Katta General Hospital, Miyagi 989-0231, Japan
Abstract. This study aimed to focus on the role of radiologists in the diagnosis and management of adrenal lesions, particularly primary aldosteronism (PA) and secondary hypertension. As hypertension affects more than one-third of the population in Japan, identifying secondary causes such as PA and adrenal lesions is crucial. Establishing a radiological differential diagnosis of adrenal lesions using advanced imaging techniques, such as computed tomography and magnetic resonance imaging, is crucial. Knowledge of the imaging findings of various benign and malignant adrenal lesions, such as adrenocortical adenomas, cortisol-producing lesions, pheochromocytomas, adrenocortical carcinoma, malignant lymphoma, and metastatic tumors, is necessary. Adrenal venous sampling (AVS) plays a crucial role in accurately localizing aldosterone hypersecretion in PA, especially when imaging fails to provide a clear diagnosis. This paper details the technical aspects of AVS, emphasizing catheterization techniques, anatomical considerations, and the importance of preprocedural imaging for successful sampling. Furthermore, we explore segmental adrenal venous sampling (SAVS), a more refined technique that samples specific adrenal tributary veins, offering enhanced diagnostic accuracy, particularly for microadenomas or challenging cases that may be missed with conventional AVS. The methodology for performing SAVS, along with the interpretation criteria for successful sampling and lateralization, is also outlined. Furthermore, radiologists have initiated treatments for unilateral PA, such as radiofrequency ablation, and play an integral role in the management of adrenal lesions. Collaborative approaches across clinical departments are required to enhance patient management in medical care involving the adrenal gland.
Key words: Primary aldosteronism, Segmental adrenal venous sampling, Adrenal imaging techniques, Secondary hypertension management, Aldosterone producing adenoma
Introduction
Adrenal diseases often involve elevated hormone levels, and for accurate diagnosis and management, a thorough understanding of both clinical and imaging approaches is necessary. Many adrenal disorders are associated with hypertension. When hypertension has no identifiable cause, it is known as essential hypertension, while hypertension resulting from specific causes is referred to as secondary hypertension. Secondary hyper-
tension accounts for approximately 20% of all hyperten- sion cases. Primary aldosteronism (PA), originating from the adrenal gland, was previously considered a rare dis- ease, but it has been recognized as a highly frequent cause of hypertension, accounting for approximately 10% of all hypertension cases [1-5]. Cushing’s syndrome (CS) and pheochromocytomas are also known to cause secondary hypertension [6-13].
On the other hand, recent advancements in high spatial resolution by computed tomography (CT) have led to an increase in the detection of adrenal incidentalomas, par- ticularly among the aging population. Generally, the prevalence of adrenal incidentalomas detected during abdominal CT scans are reported to be up to 3-8% [14-17]. Among adrenal incidentalomas, non-functional adenomas are the most common, accounting for 51% of
E-mail: kei.takase.a6@tohoku.ac.jp
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cases. Cortisol-producing adenomas are reported to occur in about 11% of cases, while aldosterone- producing adenomas account for around 5% [18]. At the time of diagnosis, the average diameters of non- functional adenomas, cortisol-producing adenomas, and aldosterone-producing adenomas are approximately 2.4 cm, 2.8 cm, and 1.5 cm, respectively [18, 19]. How- ever, it is important to note that other benign lesions, including non-tumorous diseases, can also be detected. Primary adrenal malignancies also occur, and adrenal metastases are common; these differential diagnoses are clinically needed [15, 20-24]. Magnetic resonance imag- ing (MRI) can detect small tumors and their characteris- tics, including intra- and extracellular lipids, which may make it possible to differentiate adrenal lesions.
PA caused by unilateral hypersecretion can be com- pletely cured or improved by adrenalectomy, following adrenal venous sampling (AVS), which localizes aldo- sterone hypersecretion [25-39]. AVS can be a challeng- ing procedure for radiologists, but our group has extensively studied the imaging anatomy of the adrenal veins, experienced over a thousand AVS cases, and led physician-initiated clinical trials of percutaneous radiofrequency ablation (RFA) for aldosterone-producing adenomas (APAs) in the nation. Thus, we are recognized as one of the leading facilities in adrenal management. In this review, the general principles of imaging-based diag- nosis of major adrenal tumors and details of the technical aspects of AVS using CT were outlined, emphasizing the increasingly important role of radiologists in the diagno- sis and management of adrenal lesions.
Imaging features of adrenal benign lesions
Adrenal adenomas
When an adrenal nodule is present, it is crucial to determine whether it is an adenoma, most of which do not exhibit hormone overproduction. Benign adrenocorti- cal adenomas contain intracytoplasmic lipids and tend to appear on specific images. They show low density, typi- cally <10 Hounsfield units (HUs) in non-contrast CT, with a high sensitivity of 71% and a specificity of 98% in a previous meta-analysis [40]. In dynamic CT imag- ing, adenomas demonstrate early-phase mild enhance- ment and late-phase washout at 60-75 s and 10-30 min post-contrast injection, respectively, unlike non- adenomas (Fig. 1). An absolute percentage washout of >60% and a relative percentage washout of >40%, calcu- lated from unenhanced and contrast-enhanced CT images, serve as typical thresholds for adenomas. These criteria offer high sensitivity (82-100%) and specificity (83-100%) for detecting lipid-poor adenomas [41]. However, this adrenal washout CT may produce false
negatives or false positives, including cases of pheochro- mocytomas [42, 43]. In tumors that exhibit >10 HUs on non-contrast CT scans, chemical shift MRI can detect lipids more sensitively, with a sensitivity of 67% and a specificity of 100% [44]. Adenomas can show lower signal intensity in the opposed phase compared with the in-phase [16, 22, 41, 45-50]. Beyond these indicators, images provide more information, such as the hetero- geneity of the contrast effect and the presence of cysts, hemorrhage, and necrosis. Despite various diagnostic efforts, a definitive diagnosis remains elusive for some adenomas, necessitating a comprehensive assessment that includes laboratory tests and image monitoring over time.
Cortisol-producing lesions: diverse manifestations and imaging features
Whether due to adenoma or hyperplasia, enlargement of the adrenal glands while maintaining their morphol- ogy and oversecretion of cortisol can induce CS or sub- clinical CS (SCS) without the typical physical signs of CS [9]. Adrenal adenomas can grow up to approximately 4 cm in size in patients with CS or SCS [51]. Cortisol- producing adenomas can suppress the ACTH released by the pituitary gland; therefore, the regular cortical parenchyma may become thin and atrophic. In rare cases, diseases that manifest with symptoms similar to Cushing’s syndrome can cause enlargement of the adrenal gland. This is mostly attributed to pituitary- dependent Cushing’s disease, while even more rarely, it can be caused by bilateral macronodular adrenocortical disease (BMAD) (Figs. 2, 3) [6, 7, 52]. Another cause is primary pigmented nodular adrenocortical disease (PPNAD), which predominantly occurs in infants and young adults. PPNAD presents as multiple small nod- ules [8]. Overall, 131 I-adosterol scintigraphy (which uses the radioactive tracer 131I-6beta-iodomethyl-19- norcholesterol) shows a strong accumulation in cortisol- producing lesions. However, it may not accurately depict bilateral normal adrenal glands for suppression. On the other hand, bilateral hyperplasia, BMAD, and PPNAD show a strong bilateral accumulation.
Other benign adrenal lesions
Common benign adrenal lesions include myelolipo- mas, cysts, adrenal hematomas, and ganglioneuromas. Myelolipomas are diagnostic for coarse lipid density (<0 HU) and soft tissue density mass on unenhanced CT (Fig. 4) [20, 41, 45, 46, 53]. However, in very rare cases, adenomas could have some lipid density [54]. Cysts are characterized by their non-enhanced homogeneous internal density (10-20 HUs) and thin walls on CT [41, 46]. On MRI, cysts display fluid-like characteristics with high signal intensity on T2-weighted image (T2WI) and
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(a) A low-density tumor (0 HU) with a smooth margin is observed in the non-contrast CT scan.
(b) In the dynamic study, the tumor shows enhancement in the early phase (115 HU), (c) followed by washout in the delayed phase (39 HU). The washout rate is calculated as 66%: (115-39)/(115 -0) × 100.
(d. in-phase, e. out-of-phase) Out-of-phase T1-weighted MRI shows signal degradation, indicating the presence of a fat-containing tumor mass, which suggests adenoma. Despite measuring 3.5 cm, larger than the threshold of 3 cm, the tumor was confirmed as an aldosterone-producing adenoma.
(f-j) A 55-year-old female with left adrenocortical carcinoma.
(f) A moderate-density tumor (31 HU) with a smooth margin is observed in the non-contrast CT scan.
(g) The dynamic study shows tumor enhancement in the early phase (169 HU), (h) but poor washout in the delayed phase (120 HU). The calculated washout rate is 36%: (169 - 120)/(169- 31) × 100.
(i. in-phase, j. out-of-phase) Signal degradation does not occur in the out-of-phase T1-weighted MRI. Adrenocortical carcinoma is histologically confirmed after total resection.
low signal intensity on T1-weighted image (T1WI), simi- lar to cerebrospinal fluid, with the thin walls.
Adrenal hematomas can arise from blood coagulation disorders, trauma, infection, or spontaneously. The appearance of these hematomas can vary, being either homogeneous or heterogeneous. Typically, they show a slight increase in density on CT images and relatively high signals on both T1WI and T2WI on MRI. An older hematoma may display calcifications with high density on CT and/or a distinctly low signal on T2WI due to hemosiderin deposition [41, 46].
Ganglioneuroma is a benign tumor comprising gan- glion cells, nerve fibers, and Schwann cells, without neu- roblast cells. It is considered the final stage of naturally regressed/mature neuroblastoma [55]. It may show non- specific soft tissue density and punctate calcification on CT images. In MRI, myxoid tissue is usually indicated
by homogeneous or heterogeneous moderate-to-high sig- nal intensity on T2WI and low signal intensity on T1WI. The lesion may gradually be enhanced on dynamic MRI.
Paraganglioma/pheochromocytoma
Paragangliomas are non-epithelial neuroendocrine neoplasms that primarily produce catecholamines. Paragangliomas arise from sympathetic and parasympa- thetic paraganglia. The term pheochromocytoma is used specifically for intra-adrenal paragangliomas [56]. All pheochromocytomas are considered potentially malig- nant. Historically, these tumors were referred to as the “10% disease,” with the assumption that approximately 10% were malignant. However, recently, when pheochromocytoma is suspected, it is regarded as poten- tially malignant, leading to the recommendation for
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surgical excision in all cases [56]. They typically present as tumors >3 cm in diameter, although smaller tumors also exist and show early avid enhancement owing to high vascularity and late washout in dynamic studies. They have higher signals on T2WI than adenomas (Fig. 5). Necrotic and cystic forms and enlarged surrounding vessels are often observed, particularly in larger masses. I-123 metaiodobenzylguanidine (MIBG) scintigraphy has a sensitivity of 90% and a specificity of 80-90%, proving its high diagnostic efficacy (Fig. 5) [57]. Pheochromocytomas can vary in their morphology and function. Some may be heterogeneous due to hemor-
rhage and degeneration (Fig. 6). Others may be multifo- cal or small, not show increased MIBG uptake, or not secrete catecholamines [11]. However, when an adrenal tumor is identified and cannot be definitively diagnosed as an adenoma, measuring catecholamine levels is still useful for diagnosing a pheochromocytoma, regardless of imaging findings [10, 11, 58]. Performing a biopsy carries the risk of inducing a hypertensive crisis [15].
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(a) A well-defined nodular tumor measuring 17 mm is observed in the right adrenal gland on the T1-weighted image. The lesion appears uniformly isointense on the T1-weighted image (arrow). (b, c) The tumor demonstrates early-phase enhancement and shows washout in the delayed phase. (d, e) An I-123-metaiodobenzylguanidine (MIBG) scan (anterior view) demonstrates high uptake in the tumor.
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(a) The CT scan demonstrates an enhanced tumor with multiple cystic components and calcification. (b) I-123 metaiodobenzylguanidine (MIBG) scintigraphy (anterior view) reveals high uptake.
Imaging findings of other malignant adrenal lesions
Adrenocortical adenocarcinoma
Adrenocortical carcinoma is rare, with fewer than one person per 100,000 newly diagnosed cases annually. In adrenocortical carcinoma, tumors are >4 cm in 90% of cases and >6 cm in 70% of cases [59-61]. Functional tumors are observed in 60% of cases and are often
accompanied by CS or SCS. They may secrete sex hor- mones, causing feminization or virilization. Adrenocorti- cal carcinomas show heterogeneous densities due to necrosis and hemorrhage on CT. Their heterogeneous high signal intensity is also observed on T2WI, and high signals on T1WI can be seen due to areas of necrosis and hemorrhage. Image findings suggestive of a malignant tumor includes an irregular contour of the tumor, loss of fat tissue between the mass and surrounding structures
such as the diaphragm or kidney, and intravenous tumor thrombi [62]. Biopsies often make it difficult to distin- guish between benign and malignant tumors; therefore, the Weiss score should be determined after complete tumor excision [62].
Malignant lymphoma
Primary adrenal lymphoma is extremely rare, account- ing for less than 0.7% of adrenal masses and 0.1% of all lymphomas that are confined to the adrenal glands and typically involves both glands bilaterally [63, 64]. In contrast, adrenal involvement in systemic lymphoma, which is often unilateral, was found in 24% of dissemi- nated non-Hodgkin’s lymphoma cases in an autopsy study [65]. In ultrasonography, lesions present a uni- formly hypoechoic area, and on CT and MRI images, lesions are typically depicted as homogeneous. A key diagnostic feature is the high signal intensity on diffusion-weighted imaging, accompanied by low ADC values on MRI [66]. The presence of traversing blood vessels suggests a softer tumor consistency, which is a characteristic of malignant lymphoma. Prompt needle biopsy is recommended for diagnosis when malignant lymphoma is suspected [57].
Adrenal metastasis
Adrenal metastasis is commonly observed, and 50% of the adrenal masses in patients with malignancies are metastases [15, 23]. Although bilateral adrenal lesions raise a high suspicion of metastasis, approximately half of adrenal metastases present as unilateral lesions [67]. Among cancers that metastasize to the adrenal glands, lung cancer is most prevalent, accounting for 35% of cases, followed by cancers of the stomach, esophagus, and liver/bile ducts, emphasizing the need for a thorough evaluation of these primary sites in patients presenting with adrenal masses [67]. Metastatic lesions do not show as low density as adenomas on plain CT and exhibit het- erogeneous enhancement. Out-of-phase signals on MRI do not diminish for metastases, except those from lipid- containing renal cell carcinomas and hepatocellular car- cinomas [17, 41, 45, 46]. Although benign lesions can grow, their growth rate typically differs from that of adrenal malignancies, which is a critical findings in the clinical diagnosis of metastases. The presence of 131 I- adosterol scintigraphy accumulation in the lesion can rule out metastasis [68].
On positron emission tomography (PET), increased accumulation of 18-fluorodeoxyglucose (FDG) in the adrenal nodules can be detected during work up for malignancy or even incidentally. A maximum standard- ized uptake value of 3.1 is used as a cutoff, providing high diagnostic value for distinguishing benign and
malignant lesions [69]. However, importantly, benign adenomas can also demonstrate higher FDG uptake [70].
Adrenal diagnostic imaging in primary aldosteronism
More than 98% of PA cases are either idiopathic hyperaldosteronism (IHA), which is a bilateral adrenal hyperplasia, or APA, which typically involves a single gland [32]. Other cases include unilateral hyperplasia, aldosterone-producing adrenocortical adenocarcinoma, and familial hyperaldosteronism type 1, also known as glucocorticoid-responsive aldosteronism (GRA) [32]. As unilateral PA can be cured by adrenalectomy on the affected side and bilateral PA is treated with pharma- cotherapy, it is essential to distinguish APA from IHA. However, the presence of non-functional adenomas, par- ticularly in IHA, and CT- or MRI-undetectable unilateral small lesions make it difficult to accurately distinguish based on morphological and functional imaging alone.
Representative reports showed that the overall accu- racy of diagnostic CT for PA localization was 53-55% [35, 71]. According to a previous study, 22% of patients would have been incorrectly excluded as candidates for adrenalectomy, and 25% might have undergone unneces- sary adrenalectomy if decisions were made based solely on CT findings without AVS [35]. This determination relies on morphological imaging. Additionally, in a 2006 report by Omura and Nishikawa et al., the postoperative cure rate of hypertension was higher in patients with CT- negative micro-APA compared to those with CT-positive macro-APA. This emphasizes the importance of accu- rately identifying and surgically treating these small lesions [72]. For optimal treatment of PA, accurate local- ization is essential in determining which adrenal gland is secreting excessive aldosterone [27, 30, 33, 34, 72-74].
Challenges of imaging in aldosterone- producing adenoma detection and diagnosis
APA is generally small, with a mean diameter of 1.0- 1.5 cm (Fig. 7) [64, 73-77]. The normal adrenal cortex usually remains intact in patients with PA. Even with modern imaging technology, small adrenal tumors (<5 mm) are often undetectable by CT/MRI because of the size of the adrenal gland, and micro-APAs typically only appear in post-excision pathology [78, 79]. There- fore, APA may still be present even if CT/MRI findings reveal no lesions.
Adrenal scintigraphy using 131I-adosterol has low diagnostic accuracy for small-sized APA, regardless of dexamethasone suppression [80]. The diagnostic accuracy
and clinical effect of 131I-adosterol scintigraphy using single-photon emission computed tomography have improved, achieving an overall accuracy of 77.4% [27]. Additionally, 11C-metomidate PET-CT has been recently proven to be useful for lateralizing aldosterone secretion [26, 81]. Although PET has higher resolution than scintigraphy, it is still not fully capable of diagnosing functional microadenomas, particularly because of its limited resolution. Hormone concentration measure- ments by AVS are now considered the most reliable for localizing aldosterone hypersecretion in PA [29, 32, 35,
36, 78, 79, 82, 83].
Technical aspects of AVS and venous anatomy
Because AVS is the only reliable method for localizing PA, performing a successful AVS is of utmost impor- tance. However, AVS has been reported to be difficult, with a success rate of approximately 70% [83, 84]. Expe- rienced radiologists can achieve a 90% success rate [85]. However, some cases remain difficult, even for experi- enced personnel. We have recorded a sampling success rate of 99% from the start of the preoperative CT imag- ing at our institution [86]. Our experience suggests that increasing the success rate to this level requires a deep understanding of adrenal venous anatomy, accurate selection of the optimal catheter configuration, and appropriate shaping of it [87].
The left adrenal vein (LAV) is slightly thicker and longer than the right adrenal vein (RAV), with an aver- age diameter of 3-4.5 mm and a length of 2.5-3 cm [84, 85] (Fig. 8). The RAV is a short, thin vein averaging 3-3.5 mm in diameter and 5-7 mm in length [88, 89] (Fig. 8). However, the height, left/right position, and course of the RAV joining the IVC can vary. In some cases, RAVs flow into the accessory hepatic vein (HV) to form a common trunk, which occurs in approximately 3- 24% of cases [86, 90]. Due to the need for specific catheters for each RAV, it is strongly advised to map the RAV using dynamic contrast-enhanced CT prior to AVS (Fig. 9).
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The right adrenal vein originates in the relatively anterior superior portion of the adrenal gland, runs anteriorly, and often directly drains into the inferior vena cava at the level of the 11th/12th thoracic vertebra (arrow).
The left adrenal vein originates in the lower anteromedial aspect of the left adrenal gland, courses anteriorly and medially, and joins the superior aspect of the left renal vein (arrow).
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(a) The right adrenal vein (RAV) is clearly visible on the preoperative dynamic CT scan.
(b) The adrenal vein runs cranially from the adrenal gland and joins the inferior vena cava on the sagittal image. Therefore, a type I catheter was prepared to select it.
(c) The left adrenal vein is also clearly visible on the preoperative dynamic CT scan.
(d) The adrenal vein runs caudally from the adrenal gland and joins the left renal vein on the coronal image.
(e) In the maximum intensity projection (MIP) image, arrows are placed at the inflow points of the left and right adrenal veins to easily evaluate the relationship between the veins and the bones. The catheter is manipulated with reference to this image.
(f, g) The relationship between the inflow points of the bilateral adrenal veins and the bone in angiography matches well with the MIP image.
Protocol of CT before AVS
Thin and short RAVs should be examined using an optimized protocol to ensure their delineation. The most comprehensive CT protocol encompasses a non-contrast phase, followed by a four-phase scan that includes early arterial, late arterial, venous, and delayed phases [86, 91]. For example, the timing of the early phase is deter- mined by the bolus-tracking method: the late arterial phase starts 13 s after the early phase, and the venous and delayed phases start 70 and 180 s, respectively, after the start of a 25-second contrast injection. Late arterial phase images alone can detect 95% of RAVs, while all images combined can detect 97% [90]. Accessory HVs are not yet opacified and therefore do not prevent RAV delineation in this phase, whereas HVs themselves can be easily evaluated in the venous or delayed phase [91]. It is important to identify any rare anatomical variations, such as left-sided IVC or duplication and iliac or femoral vein stenosis. In an effort to reduce radiation exposure, options include the omitted protocol, the use of low- voltage CT scanning, and non-contrast MRI [92].
The following parameters are recorded based on the study of Matsuura et al. [90]:
1. Height of the RAV confluence: location of draining into the IVC relative to the vertebral body
2. Location of draining into the IVC on the axial view: draining angle relative to the IVC
3. Course of the RAV: lateral, medial, upward, or downward
4. Relation to the accessory HV: relative location, trunk common with the accessory HV and RAV
During AVS, catheterization of the RAV is usually performed under shallow breathing conditions with mini- mal respiratory movement; thus, expiratory-phase CT is recommended.
Adrenal venous sampling catheterization procedure
In AVS, there are two methods: simultaneous and sequential sampling, which involve the bilateral and uni- lateral femoral approaches, respectively [87, 93]. For diagnosis using non-ACTH-stimulated sampling results, it is necessary to perform simultaneous bilateral sam- pling within approximately 15 min to minimize the effect of timing differences, making the bilateral method more advantageous. Catheterization of the LAV often involves
time-consuming maneuvers that require catheter exchange and careful repositioning, which can lead to potential delays in the procedure. Therefore, it is advisable for an inexperienced operator to use a method that allows the placement of catheters in both adrenal veins, as it helps avoid challenging situations. Depending on the catheter used, a 7F or 5F sheath is inserted.
There are a few methods available for administering ACTH, along with appropriate dosages [94, 95]. In the AVS procedure at our institution, 200 µg of ACTH is administered as a bolus following the initial blood col- lection. This is followed by an infusion of 50 µg/h, start- ing 30 min after the bolus administration and continuing until the completion of sampling from the tributary veins [87].
Left adrenal vein catheterization
The catheters commonly used to cannulate the LAV are S-shaped with two opposing curves, available in sizes of 5F or 6.5F, with different shapes and stiffnesses (Fig. 10a). To invert the catheter tip of the LAV catheter, it is recommended to advance the catheter into the con- tralateral iliac vein. Once the wire is advanced into the contralateral iliac vein, it allows the LAV catheter to be inverted at the iliac bifurcation. Using the curvature of the catheter tip designed for the RAV can be an option for advancing the wire. Advancing catheters into the right atrium is another method, however, it is not recom- mended due to the risks of catheter entanglement and complications during removal associated with the Chiari network, a congenital remnant of the right sinus venosus valve [96].
In most cases, the LAV, which is typically a single
vessel, merges with the left inferior phrenic vein (LIPV). The segment before the LIPV junction is termed the common trunk or conjunction, whereas the portion beyond it, which is central to the tributaries of the adrenal vein, is the adrenal central vein. Blood sampling, often performed with microcatheters, risks unintended superselective sampling from the LIPV or peripheral tributaries of the adrenal vein. To mitigate this, a left anterior oblique view is advised to reduce the chance of overlap with the left central vein and LIPV observed in the posteroanterior view, which can lead to improper sampling [87, 97].
There is a debate regarding the appropriate left sam- pling sites, the common trunk and adrenal central vein, with discrepancies evident across guidelines [78, 79]. Sampling from the common trunk can show a significant dilution of the adrenal blood by extra-adrenal blood from the LIPV, which can result in samples not meeting the criteria for successful sampling. Sampling from either site can overlook aldosterone laterality due to APA [78, 79]. Variations in the LAV are rare; however, occasion- ally, a portion or most LAV blood may drain into the renal capsular or gonadal vein. Additionally, the pres- ence of the left lateral tributary proximal to the LIPV junction and rare instances where the LIPV directly joins the renal vein can affect the diagnosis during AVS [98, 99].
RAV catheterization
The difficulty in sampling the RAV is largely attributed to its thin and short anatomy, as well as the abundant variation in its course. This variability makes it impossible to use a single type of catheter for
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Fig. 10 Variations of the adrenal vein and the corresponding optimal catheter type (a) Catheter for the left adrenal vein.
(b) Most typical right adrenal vein (RAV) and type I catheter
(c) Upward RAV and type II catheter
(d) RAV joining the central posterior quadrant of the inferior vena cava (IVC) and type III catheter
(e) RAV runs from the right to left side of IVC and type IV catheter
(f) RAV forming a common trunk with an accessory hepatic vein (HV) and “accessory HV”-type catheter
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cannulation in all cases. Based on our previous analyses, we have developed five types of three-dimensional pre- shaped catheters specifically designed for the RAV (Fig. 10b-f). Paradoxically, understanding these catheter shapes can also enhance our understanding of RAV anatomy. For the operator, it is more intuitive to describe the RAV direction from the IVC, even though these directions are opposite from a hemodynamic perspective.
Most RAV openings into the IVC are located on the dorsal side, either at the right lateral edge or slightly medial to it. The majority, accounting for 77%, are ori- ented posteriorly and to the right. In the sagittal plane, 89% are oriented caudally from the openings, as reported in a previous study [86]. For this specific orientation of the RAV, a type I catheter is suitable (Fig. 10b). Using this catheter alone can result in successful RAV sam- plings in most cases.
The upward course of the RAV from its opening is observed in 7-21% of cases [86, 90]. In these situations, a type II catheter with an obtuse angle is used. RAVs that connect to the IVC in the central posterior quadrant are observed in 3-31% of cases [86, 90], and for this type, a type III catheter is used. In the axial plane, when the RAV runs from the right to the left side of the IVC, it is appropriate to use a type IV catheter (Fig. 10c-e). Even if a catheter similar to type I is used for this type of RAV, it is often difficult for the catheter tip to engage. Types III and IV have shapes that add curves in the opposite direction to the first and second curves of type I, respec- tively. Although a two-dimensional (2D) catheter, such as the Cobra type, which is familiar to radiologists, may fit RAVs, maneuverability can be significantly poor if the IVC has an elliptical cylindrical shape (as the
catheter tends to orient in the larger left-right direction), and cannulation may be hindered.
Although the RAV opening may be similar in position for these types, if the course of the RAV and the shape of the catheter do not match, it may not be possible to can- nulate the vein. Even if cannulation is possible, the catheter may wedge against the vessel wall, preventing blood sampling or, in the worst case, causing extravasa- tion during contrast injection. Countermeasures that con- tribute to successful sampling include appropriate selection of catheters, fine-tuning the angle by steam- shaping the catheter tip (Fig. 11), cutting the tip into a small wedge shape, and using a microcatheter with a slit. Moreover, the pre-shaped catheters mentioned above are equipped with side holes to prevent vascular damage when inserted. Alternatively, even without these side holes, one can easily create them by piercing a 24G nee- dle into the tip at a single point.
For the cases that RAVs form a common trunk with an accessory HV, an “accessory HV”-type catheter can be inserted into the accessory HV and turned slightly counterclockwise to guide it into the RAV (Fig. 10f). In cases where the RAV joins the caudal aspect of the HV, this posterior-facing catheter may not be suitable, and a J-shaped catheter may be appropriate (Fig. 12). If the common trunk of the HV and the RAV is very short, the type I catheter would be suitable.
In rare anatomical cases, two RAVs may exist, and because their drainage areas can differ, sampling from only one may not capture high aldosterone levels from an APA [100, 101]. Moreover, the RAV is rarely conflu- ent with the right renal vein [102]. Proper identification of these variations is critical for AVS success.
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The arrow highlights the RAV flowing into the accessory HV. The RAV is catheterized using a J-shaped catheter (arrow) on CT images.
(b) Retrograde angiography of the RAV.
Although alternative catheters, such as the Cobra type or other 3D-shaped catheters, were used, they were not stable during respiration and tended to dislodge. Ultimately, the J-shaped 4F catheter (RC2 Medikit, Tokyo, Japan) provided the most stability for blood sampling (arrow). Catheter stability is crucial, especially when sampling from tributaries after central venous blood collection.
In precise AVS of the RAV, a right anterior oblique position of approximately 20-40° may be more useful than a front view because it allows for a longer view of the central vein. Furthermore, during the examination, it is essential to provide the patient that shallow breathing is required after catheter insertion and before and after digital subtraction angiography (DSA), as deep breathing may dislodge the catheter. This instruction should be provided before the procedure, as some patients may become drowsy during examination.
Distinguishing between the accessory HVs and RAVs
A thick accessory HV can be easily distinguished from the RAV; however, a fine accessory HV sometimes looks like the RAV and may present the risk of incorrect sam- pling. HVs should be differentiated from the adrenal veins based on the following characteristics: The acces- sory HV typically possesses anastomoses with other HVs in the upper medial (central) direction, which can usually be confirmed using venography (Fig. 13a), although RAVs sometimes connect to the HVs or the portal vein at the periphery of the adrenal gland. Patchy and dense stains of the hepatic parenchyma are also useful for dif- ferentiation (Fig. 13a, b). The adrenal tributary veins show a triangular distribution, particularly in the right anterior oblique view, without prominent parenchymal enhancement (Fig. 13c). Anastomosis between the RAV and renal capsular vein along the contour of the kidney is another notable feature. Careful observation reveals the
outline of the kidney on fluoroscopic images, which sig- nificantly reveal the positional relationship between the RAV and right kidney.
CT during arteriography for RAV visualization
There may be instances in which the RAV remains elusive despite various attempts, and CT during arteriog- raphy may be beneficial in overcoming this situation [101]. Once arterial access is secured and the right adrenal artery is selected using a microcatheter, DSA confirms good visualization of the adrenal gland, and the RAV is depicted during the venous phase. Although the RAV can be difficult to observe as it may overlap with the staining of the adrenal parenchyma on DSA, subse- quent CT imaging during arteriography will clearly delineate the RAV, increasing the chances of successful AVS.
Interpretation of the sampling data
The interpretation of the AVS results can be divided into two steps: confirmation of successful AVS and localization. Especially on the right side, a blood sample that is intended to be an RAV sample may actually be an IVC or HV sample incorrectly, which means that RAV sampling has failed [103]. AVS success is determined by the selectivity index (SI), which is calculated by dividing the cortisol level in the adrenal vein by that in the periph- eral blood. An SI of ≥2 without ACTH stimulation and an SI of ≥3 or 5 with ACTH stimulation are commonly
a
b
C
Fig. 13 Venography of small accessory hepatic veins (HVs) mimicking the right adrenal vein (RAV) (a) An accessory HV is visible, connected to other HVs through anastomotic veins (arrow). There is also a dark stain observed (arrowhead).
(b) Another accessory HV also exhibits a dark stain (arrowhead).
(c) The RAV is characterized by tributaries that do not connect to the HV or display any dark staining. However, there is an anastomosis with the renal capsular vein (arrow).
considered indicative of successful sampling [97, 100, 104]. If these criteria are not met, determination of later- ality is not recommended.
The lateralization ratio (LR), or lateralization index, is defined as the ratio of adrenal venous aldosterone to cortisol (A/C) on the dominant side divided by the con- tralateral adrenal central vein A/C [35, 104, 105]. Recent guidelines have set LR >4 for unilateral PA after ACTH stimulation [104, 105]. A typical bilateral PA demon- strates an LR <2. However, an LR of >2 and <4 is con- sidered “gray zone,” which includes unilateral PA; thus, the decision must be comprehensive, considering clinical findings. Moreover, these cutoffs may vary among insti- tutions, and the use of ACTH remains controversial. It should be noted that the cutoffs in AVS might change because the non-radioimmunoassay (RIA) method, specifically the chemiluminescent enzyme immunoassay (CLEIA) method, has been recently used to measure plasma aldosterone concentration [106].
In the interpretation of AVS, it is important to consider that blood containing hormones overproduced by APA may mix with blood from other suppressed areas, poten- tially resulting in lower hormone levels in the central vein.
Segmental adrenal venous sampling
The greatest drawback of conventional AVS is its potential to miss unilateral PA, often due to the tumor blood not passing through the central vein or being diluted [107]. This issue can be mitigated by using seg- mental AVS (SAVS), which involves venous sampling specifically from the adrenal tributary veins [108]. This
targeted sampling, ideally from at least two or preferably three distinct regions, creates a clearer contrast between regions with high and low aldosterone secretion, enhanc- ing diagnostic confidence compared to central venous sampling alone. SAVS may add difficulties in micro- catheter manipulation compared to conventional AVS, with issues such as extended time and increased expo- sure. Contrast injections in thin tributaries can sometimes cause minor extravasation, even when administered by experienced radiologists. Although SAVS is still consid- ered a non-standard technique, recent literature high- lights its growing international recognition, particularly for improving diagnostic accuracy in PA [109, 110].
Even when unilateral PA is diagnosed on conventional AVS, it is challenging to confirm whether the lesion visualized on imaging is actually responsible for aldo- sterone secretion. This is particularly important when considering partial adrenalectomy or CT-guided RFA of adrenal adenomas, since confirming that no disease remains in the residual adrenal tissue is crucial. SAVS have also made it possible to differentiate between IHA and bilateral APA [87, 108]. In IHA, all venous samples typically show high levels of aldosterone. In contrast, in bilateral APAs, elevated or suppressed concentrations of aldosterone are observed in the presence or absence of tumoral blood, respectively. Interestingly, there are cases referred to as “double down” cases, where bilateral aldosterone suppression is observed in AVS results. This means that the bilateral adrenal venous A/C ratios are lower than the peripheral venous A/C ratios. In such cases, a diagnosis of unilateral APA can be made using SAVS [87, 111].
a
b
C
d
e
f
Fig. 14 Bilateral aldosterone-producing adenoma (a, b) Multiple adrenal adenomas (arrows) are observed bilaterally on the CT scan of a 49-year-old male. (c-f) Adrenal venous sampling was conducted using a microcatheter through the right and left adrenal venography. Superselective venography was performed on the right lateral and inferior tributaries. (e, f) The left superior tributary (arrowhead) exhibited a low aldosterone level, indicating the presence of a normal adrenal cortex in the left upper portion. Conversely, all other tributaries (arrows) showed high aldosterone concentration. This patient was successfully treated by undergoing a right total adrenalectomy combined with a left lower partial adrenalectomy.
Our diagnostic approach is based on comparing the peripheral A/C ratio with that in the tributary veins, con- firming overproduction in areas where the A/C ratio is higher than the peripheral value and suppression when it is lower. Furthermore, SAVS can be evaluated using absolute aldosterone values, with studies showing that APAs can be accurately identified when aldosterone levels in tributary veins exceed 38,780 pmol/L (14,000 pg/mL), which is particularly advantageous when cortisol sup- pression occurs in the adrenal cortex due to a cortisol- producing adenoma [112]. Moreover, detailed examination of the contralateral adrenal gland using SAVS has been shown to correlate with postoperative complete biochemical success, even where total adrenalectomy was performed [76]. It should be noted that this threshold for aldosterone excess is based on a former measurement method, and the value may differ with the current CLEIA method, which requires further evaluation to establish updated reference standards.
Treatment based on AVS results
When unilateral PA is confirmed, curative treatment for hypertension can be expected through unilateral adrenalectomy of the affected side. This procedure is
usually performed via a retroperitoneal or laparoscopic approach, with >80% of patients experiencing normal- ization or improvement in blood pressure, and a bio- chemical cure rate of 94% is reported [104]. Complete clinical success is defined as normal blood pressure with- out the aid of antihypertensive medication, while partial clinical success involves the same blood pressure with less antihypertensive medication or a reduction in blood pressure with either the same or less medication. Absent clinical success is characterized by unchanged or increased blood pressure with the same or increased medication [113].
Although partial adrenalectomy is an option for surgi- cally feasible cases of cortisol producing lesions or pheochromocytoma, it is not generally recommended for PA because of the potential for residual microadenomas in the operated adrenal glands. However, SAVS has demonstrated heterogeneity, and in situations where the possibility of a residual tumor in the remaining adrenal gland can be excluded, results comparable to those of total adrenalectomy have been reported [114].
Regarding the treatment of unilateral lesions, surgery following medical treatment has been reported to result in better PA control [115, 116]. However, further investi- gation is needed to compare the long-term outcomes of
medical therapy, surgery, and their combination. In cases where bilateral hypersecretion is observed, the optimal medical treatment is chosen, but in bilateral APA cases, partial adrenalectomy may be considered as a surgical option to resect APAs while preserving adrenal hormone production (Fig. 14). Furthermore, interventional tech- niques, such as RFA for APA, have become increas- ingly successful [75, 117-119]. The cure rate for RFA in multicenter prospective trials was 86.5% (95% confi- dence interval, 72.0-94.1%). Adrenal arterial emboliza- tion has an 80% success rate in treating PA [120], and recent attempts have been made for transvenous RFA [121, 122]. Radiologists also play a role in advancing minimally invasive medical treatments for managing PA.
Conclusions
In today’s medical care involving the adrenal gland, radiological diagnostics play a crucial and extensive role in patient management. This includes selecting imaging modalities such as CT, establishing protocols, making qualitative imaging diagnoses of adrenal nodules, per- forming appropriate AVS, and determining subtypes for treatment with RFA. While there are still some unre- solved issues, recent years have seen a greater under-
standing of endocrine and radiological adrenal diseases. To achieve improved patient management, it is important to emphasize close cooperation rather than relying solely on individual clinical departments’ independent efforts.
Disclosure
None of the authors have any potential conflicts of interest associated with this research.
Author Contribution
Type of contribution of the authors:
1) Substantial contributions to the conception or design of the work or the acquisition, analysis, or interpreta- tion of data; SO, HT, HO, HK, KO, YT, YO and KT
2) Drafting the work or reviewing it critically for impor- tant intellectual content; SO, HT, HO, HK, YT, KO, YT, YO and KT
3) Final approval of the version to be published; SO, HT, HO, KS, HK, YT, KO, YT, YO, FS, SI, TT, HK and KT
4) Agreement to be accountable for all aspects of the work in ensuring that question: SO, HT, HO and KT
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