Original ResearchFree Access

Adrenal Nodules Detected at Staging CT in Patients with Resectable Gastric Cancers Have a Low Incidence of Malignancy

Published Online:https://doi.org/10.1148/radiol.2021211210

Abstract

Background

Guidelines recommending additional imaging for adrenal nodules lack relevant epidemiologic evidence.

Purpose

To measure the prevalence of adrenal nodules detected at staging CT in patients with potentially resectable gastric cancer and the proportion of patients with malignant nodules among them.

Materials and Methods

This retrospective study included 10 250 consecutive patients (median age, 63 years; interquartile range, 53–71 years; 6884 men) who underwent staging CT and had potentially resectable gastric cancer in a tertiary center (May 2003 to December 2018). All 10 250 CT studies were retrospectively reviewed, and patients with adrenal nodules (or thickening ≥10 mm) were identified to measure the prevalence of adrenal nodules. Among patients with adrenal nodules, the per-patient proportions of malignant nodules, adrenal metastasis from gastric cancer, and additional adrenal examinations were measured. A secondary analysis was performed by using data from the original CT reports. The same metrics that were used in the retrospective review were assessed.

Results

The prevalence of adrenal nodules was 4.5% (95% CI: 4.1, 4.9; 462 of 10 250). The proportions of malignant nodules and adrenal metastasis from gastric cancer were 0.4% ( 95% CI: 0.1, 1.6; two of 462) and 0% (95% CI: 0.0, 0.8; 0 of 462), respectively. A total of 27% of the patients (95% CI: 23, 31; 123 of 462) underwent additional adrenal examination. According to original CT reports, the prevalence of adrenal nodules and the proportions of malignant nodules, adrenal metastases from gastric cancer, and additional adrenal examination were 2.7% (95% CI: 2.4, 3.0; 272 of 10 250), 0.7% (95% CI: 0.1, 2.6; two of 272), 0% (95% CI: 0.0, 1.4; 0 of 272), and 42.6% (95% CI: 36.7, 48.8; 116 of 272), respectively.

Conclusion

Although adrenal nodules were detected frequently on staging CT images of patients with otherwise resectable gastric cancer, these nodules were rarely malignant.

©RSNA, 2021

Online supplemental material is available for this article.

See also the editorial by Baumgarten in this issue.

Summary

Adrenal nodules that were detected at staging CT in patients with otherwise resectable gastric cancers were rarely malignant.

Key Results

  • ■ Among 10 250 patients who underwent staging CT and had potentially resectable gastric cancer, 462 had adrenal nodules (≥10 mm) detected at retrospective CT image review.

  • ■ Only two out of the 462 patients with adrenal nodules detected at staging CT had malignant adrenal nodules, neither of whom had adrenal metastasis from gastric cancer.

Introduction

Gastric cancer is the fifth most common malignancy worldwide, with more than 1 million new cases being diagnosed annually (1). Abdominal CT is essential for staging gastric cancer (2), in which adrenal nodules are detected frequently. Characterization of the adrenal nodules is particularly important in patients with otherwise resectable gastric cancer. Such a circumstance is not rare in Eastern Asia, where gastric cancer is common and is often detected at early stages (3).

Existing guidelines (49) on adrenal incidentaloma generally recommend performing noncontrast CT for initial nodule characterization and performing additional CT or MRI examinations with a dedicated adrenal imaging protocol, if necessary. However, even with these studies, a considerable portion of the nodules remain indeterminate regarding the differentiation between benign adenoma and malignancy, which sometimes results in a biopsy or excision being required. This is because up to one-third of adenomas are lipid poor, and there is overlap in enhancement patterns between benign and malignant nodules (1012). There has been no specific guideline regarding the management of an adrenal nodule detected during staging work-up for gastric cancer. However, a few of the guidelines (47,9) on adrenal incidentalomas have addressed the management of nodules in patients with prior malignancy, and at least one guideline (6) has explicitly stated that the same recommendations apply to the patients undergoing cancer staging.

Many practitioners are often reluctant to apply those guidelines to patients in their care (1315). The discrepancy between the guidelines and practice is attributable to the scarcity of evidence (16) that either supports or refutes such use of additional adrenal imaging. There have been few studies with a sound epidemiologic approach regarding malignant adrenal nodules in patients with cancer. Three previous studies (1719) including patients with newly or previously diagnosed cancers reported that up to 70% of adrenal nodules were malignant. The reported percentages were likely to have been overestimated because those studies included patients with diverse cancers, with some having disseminated metastases and only nodules having pathologic confirmation.

In this study, we had two main research questions. First, we aimed to assess how many patients with potentially resectable gastric cancers had adrenal nodules on staging CT images. Second, we aimed to determine how many patients with adrenal nodules had malignant nodules. Such knowledge would provide evidence on whether the current guidelines recommending additional adrenal imaging need amendment or reinforced adherence.

Materials and Methods

Study Setting

The institutional review board approved this retrospective observational study (20) and waived the requirement for patient informed consent. The study took place in a tertiary center in South Korea. The study period spanned from May 2003 to December 2018. Some of these patients participated in a study that aimed to measure the performance of CT in the diagnosis of peritoneal metastasis (21) and in a randomized controlled trial testing the efficacy of ursodeoxycholic acid for prevention of gallstone formation after gastrectomy (22). Subsets of these patients have also been included elsewhere in studies related to the performance of CT in predicting the tumor stage, CT lymphography, Helicobacter pylori, texture analysis, sentinel node navigation surgery, PET/CT with water inflation of the stomach, afferent loop obstruction, tumor protein 53 mutations, and programmed death-ligand 1 testing (2338). Our practice was typically in line with the treatment guidelines of gastric cancer (3941). We wrote this report in line with a reporting guideline (42).

Patients

Our target population was patients with potentially resectable gastric cancer (Fig 1). The term gastric cancer in our study refers to adenocarcinoma and other entities that share the eighth American Joint Committee on Cancer TNM staging system (43) (Table E1 [online]).

Patient flowchart. Unless otherwise specified, data are the numbers of                         patients. * = At the time of staging CT. † = Adrenal nodule or                         thickening (10 mm or larger) detected on staging CT images.

Figure 1: Patient flowchart. Unless otherwise specified, data are the numbers of patients. * = At the time of staging CT. = Adrenal nodule or thickening (10 mm or larger) detected on staging CT images.

To keep the target population relevant to the clinical question at hand, we included patients with endoscopically suspected gastric cancer, as well as those with pathologically confirmed cancer. First, we identified 11 743 patients with gastric cancer that was confirmed by using specimens from endoscopic biopsy or endoscopic resection. Second, we identified 133 patients with endoscopically suspected cancer, even though biopsy results were unavailable or not positive for cancer. The second inclusion criterion was selected to reproduce clinical practice, wherein practitioners proceed with resection even without pathologic confirmation if endoscopic findings are highly suggestive of cancer. A false-negative endoscopic biopsy result is not rare, particularly in Borrmann type IV gastric cancer (44).

We then excluded 366 patients who did not undergo staging CT, defined as CT performed within the 3 months before any definitive treatment (ie, surgery or chemotherapy) for gastric cancer or within the 3 months before or after the performance of endoscopic biopsy or resection. We further excluded 1260 patients who had unequivocal extra-adrenal metastasis from gastric cancer at the time of staging CT for whom characterization of an adrenal nodule would not be critical for the patient disposition. All 1260 patients had image findings of extra-adrenal metastasis that was indisputably pathognomonic according to the assessments of both of two radiologists (H.Y.K., W.C.; 6 and 10 years of experience, respectively). Those 1260 patients had no documented cancer other than that from the stomach, and 445 of them had their metastases proven pathologically at the time of staging work-up. The remaining 10 250 patients formed our final study sample, representing the target population of patients with potentially resectable gastric cancer. We did not exclude patients with other prior or concurrent malignancies (n = 588). This was done not only to reflect reality but also because of concerns about the selection bias that is associated with the arbitrariness in defining metastatic cancers (eg, papillary thyroid microcarcinoma) and because of the possibility of undocumented medical history in some patients.

CT Protocol

Most patients (n = 9934) underwent staging CT in our hospital, whereas others underwent CT in other hospitals. We used various CT machines with 16–256 channels (Table E2 [online]). The image thickness was typically 4 or 5 mm. Intravenous contrast material was used in most patients (Table E2 [online]). Most patients underwent CT performed with an imaging protocol dedicated to gastric cancer staging (Table E2 [online]).

Identification of Patients with Adrenal Nodules

We define patients with adrenal nodules as those with adrenal nodules (or thickening) of at least 10 mm detected at staging CT. We used the 10-mm threshold because many guidelines (4,5,9) recommend work-up for adrenal nodules that are 1 cm or larger, and using a threshold less than 10 mm would have caused too many false-positive results (45).

For the primary analysis, we identified patients with adrenal nodules by conducting a retrospective CT image review of all 10 250 patients, which would be the closest approximation of the true prevalence. We assigned the 10 250 CT studies evenly to six abdominal radiologists (Y.H.K., Y.J.L., J.C., H.A.; 21, 14, 5, and 6 years of experience, respectively; two other radiologists who are not authors had 6 and 7 years of experience) who were informed of the study purpose. The radiologists were instructed to keep a sensitive standpoint by inclining toward judging equivocal cases as positive rather than negative. All CT images were reviewed with picture archiving and communication systems.

We added a secondary analysis to identify the patients with adrenal nodules by using the original CT reports. Although the prevalence of adrenal nodules may be underestimated in such an analysis, it may represent the reality of how adrenal nodules are detected and managed. The original reports from staging CT were issued at the time of staging in a structured form that was in line with the American Joint Committee on Cancer TNM staging system (43) and with Japanese staging guidelines (39). The form included a section for incidental findings, which was not limited to adrenal abnormality. A study coordinator reviewed the CT reports containing the term adrenal to identify patients with adrenal nodules. For some patients for whom a nodule size was not specified in the reports, the coordinator had to measure the size retrospectively to identify patients with nodules 10 mm or larger.

Management of Adrenal Nodules

During the study period, there were no uniform criteria by which follow-up examinations for the adrenal nodules were performed. We reviewed the medical records to identify patients who underwent additional adrenal examinations, which included percutaneous or excisional biopsies, further imaging, or biochemical tests.

Reference Standard

Patients with adrenal nodules were subject to reference standard adjudication by the consensus of the two adjudicators (H.Y.K., S.I.H.; 6 and 18 years of experience, respectively), who resolved any disagreement by thorough discussion. By reviewing CT images, they recorded the number, size, and laterality (right or left adrenal gland) of the nodules in each patient. Diffuse thickening of the adrenal gland or multiple conglomerated nodules were counted as one nodule.

The adjudicators made the per-nodule adjudication by using the predefined criteria (20), as detailed in Appendix E1 (online). Per-patient adjudication followed the results of the per-nodule adjudication. A patient was counted as having a malignant nodule if they had any malignant adrenal nodule. Among patients without malignant nodules, those who had indeterminate nodules were considered to have incomplete reference standards. Patients with neither malignant nor indeterminate nodules were counted as having benign nodules.

Outcome Measures

As stated earlier, we had two primary research questions. First, we aimed to determine how many patients with potentially resectable gastric cancer had an adrenal nodule at staging CT. Second, we aimed to determine how many of those patients with adrenal nodules had malignant nodules. Hereafter, we will term two outcome measures corresponding to these questions: prevalence of adrenal nodules and proportion of malignant nodules. The former would represent the proportion of patients who would have to undergo additional adrenal imaging if practitioners strictly adhered to the guidelines. The latter would represent the maximal diagnostic yield of additional adrenal imaging in the diagnosis of malignant adrenal nodules.

We also measured the proportion of patients with adrenal metastasis from gastric cancer among patients with adrenal nodules, reflecting how frequently the presence of adrenal nodules would change the patient disposition regarding the resectability of gastric cancer. We also measured the proportion of patients who underwent additional adrenal examination among patients with adrenal nodules, reflecting practitioners’ adherence to the current guidelines regarding the use of additional adrenal examinations.

Statistical Analyses

We planned all the analyses (20) before the data collection. A statistician performed the analyses. We calculated the proportions of the outcome measures and their 95% CIs. All outcome measures were analyzed on a per-patient basis. We regarded patients with incomplete reference standards as not having malignant nodules. We instead added a sensitivity analysis by assuming that the proportion of patients who had malignant adrenal nodules among those patients was five percentage points higher than that of the patients with complete reference standards. As there were too few patients with malignant nodules, we did not perform the preplanned subgroup analysis (20).

As stated earlier, we performed our primary analysis by using the retrospective CT image review data and added a secondary analysis that used the original CT reports for all our outcome measures. We expected that there would be some missing data and opted not to include missing data in the analyses. We performed all statistical analyses by using Stata 14.0 (StataCorp).

Results

Patients

Of the included 10 250 patients (Table 1), 6884 were men and 3366 were women. Their median age was 63 years (interquartile range, 53–71 years). A total of 6386 patients (62%) had gastric cancer at stage pT1, pTis, or pTX; 1199 (12%) had gastric cancer at stage pT2 (570 pN0, 629 pN+); and 1648 (16%) had gastric cancer at stage pT3 or pT4 (309 pN0, 1339 pN+). A total of 160 patients (2%) had pathologically confirmed metastasis (mostly peritoneal carcinomatosis that was either unexpected or equivocal at staging CT). There were 7802 (76%) patients who underwent gastrectomy of curative intention, and there were 1609 (16%) patients who underwent endoscopic resection (Table 1).

Table 1: Patient Characteristics, Tumor Characteristics, and Tumor Staging

Table 1:

Outcome Measures

The prevalence of adrenal nodules was 4.5% (462 of 10 250; 95% CI: 4.1, 4.9) (Table 2). The proportion of malignant nodules was 0.4% (two of 462; 95% CI: 0.1, 1.6). In the sensitivity analysis, assuming that the proportion of malignant nodules in 18 patients with incomplete reference standards was five percentage points higher than that in the patients with complete reference standards, the proportion of malignant nodules was 0.6% (three of 462; 95% CI: 0.1, 1.9) (Table 2).

Table 2: Outcome Measures

Table 2:

The proportion of patients with adrenal metastasis from gastric cancer was 0% (0 of 462; 95% CI: 0.0, 0.8). The proportion of patients who underwent additional adrenal examination was 27% (123 of 462; 95% CI: 23, 31). For adrenal nodule characterization, 65 patients underwent excisional biopsy, 25 underwent imaging, and 95 underwent biochemical tests (Table 2). All the biopsied nodules were histopathologically confirmed to be benign. The results of additional imaging were inconclusive for discrimination of malignant from benign nodules in six patients and were suggestive of benign nodules in the remaining 19.

In the secondary analyses conducted by using the original CT reports, the prevalence of adrenal nodules was 2.7% (272 of 10 250; 95% CI: 2.4, 3.0). The proportion of malignant nodules and the proportion of adrenal metastasis from gastric cancer were 0.7% (two of 272; 0.1, 2.6) and 0% (0 of 272; 95% CI: 0.0, 1.4), respectively. The proportion of patients who underwent additional adrenal examination was 43% (116 of 272; 95% CI: 36.7, 48.8).

Per-Nodule Adjudication Results and Sizes of the Nodules

A total of 522 adrenal nodules (median size, 13 mm; interquartile range, 11–16 mm; range, 10–73 mm) were detected in 462 patients during the retrospective CT image review. There were five malignant nodules in two patients, 20 indeterminate nodules in 18 patients with incomplete reference standards, and 497 benign nodules in 442 patients (Table E4 [online]). There were no patients with both benign and malignant (or indeterminate) nodules. The distribution of nodule size is shown in Figure 2. The five malignant nodules (size range, 15–31 mm) were metastases from a prior or concurrently diagnosed malignancy (lung cancer and hepatocellular carcinoma) (Figs 34). The diagnoses of 417 benign nodules in 367 patients and five malignant nodules in two patients were adjudicated on the basis of image findings (Table E4 [online]). Of those 369 patients, 361 had CT examinations before (n = 67) or after (n = 355) staging CT. The median imaging follow-up period in the 369 patients was 53.9 months (interquartile range, 27.6–65.6 months).

Stacked bar chart shows distribution of malignant (black),                         indeterminate (dark gray), and benign (light gray) nodules according to                         nodule size. For each size category, the bar on the left side shows data                         from retrospective CT image review (R), whereas the bar on the right shows                         data from original CT reports prospectively made at the time of staging (O).                         The discrepancy between R and O shows a tendency to increase with smaller                         nodule size, with the greatest difference being noted for the nodule size                         category of 10–15 mm.

Figure 2: Stacked bar chart shows distribution of malignant (black), indeterminate (dark gray), and benign (light gray) nodules according to nodule size. For each size category, the bar on the left side shows data from retrospective CT image review (R), whereas the bar on the right shows data from original CT reports prospectively made at the time of staging (O). The discrepancy between R and O shows a tendency to increase with smaller nodule size, with the greatest difference being noted for the nodule size category of 10–15 mm.

Image in a 67-year-old woman with malignant adrenal nodules.                         Contrast-enhanced transverse CT image shows 20- and 26-mm nodules (arrows)                         in the right adrenal gland and left adrenal gland, respectively. The nodules                         were adjudicated as metastasis from lung cancer.

Figure 3: Image in a 67-year-old woman with malignant adrenal nodules. Contrast-enhanced transverse CT image shows 20- and 26-mm nodules (arrows) in the right adrenal gland and left adrenal gland, respectively. The nodules were adjudicated as metastasis from lung cancer.

Image in a 56-year-old man with a benign adrenal nodule.                         Contrast-enhanced coronal CT image shows a 17-mm nodule (arrow) in the left                         adrenal gland. The nodule was confirmed as adrenocortical adenoma after                         adrenalectomy.

Figure 4: Image in a 56-year-old man with a benign adrenal nodule. Contrast-enhanced coronal CT image shows a 17-mm nodule (arrow) in the left adrenal gland. The nodule was confirmed as adrenocortical adenoma after adrenalectomy.

The per-nodule adjudication results for the 319 adrenal nodules in 272 patients identified by using the original CT reports are shown in Table E5 (online). The 319 nodules included the five malignant nodules that were detected in the retrospective CT image review.

Discussion

In this study, we found that malignancy was rare among adrenal nodules detected on staging CT images of patients with otherwise resectable gastric cancer. Among 10 250 patients, 462 had adrenal nodules. Only two of the 462 patients had malignant adrenal nodules, neither of whom had metastasis from gastric cancer.

Our results raise the question of whether additional imaging is needed for adrenal nodules detected in patients with otherwise resectable gastric cancer. Additional adrenal imaging in patients with a history of malignancy has been advocated by the guidelines on adrenal incidentaloma (47,9), which seemingly lack epidemiologic evidence. Our care providers loosely follow the guidelines, as shown by the low proportion of patients who underwent additional adrenal examination. Importantly, even after the additional imaging, differentiation of malignant versus benign nodules remained inconclusive in a quarter of the patients. The implications of our results may be cautiously extrapolated to patients without a history of malignancy. However, independent studies are needed for cancers from other origins.

It is clear from our data that additional imaging may not be necessary for the purpose of differentiating between malignant and benign adrenal nodules in patients with otherwise resectable gastric cancer. Nevertheless, some may argue that additional imaging is still necessary for further differentiation within benign nodules, particularly to rule out pheochromocytoma or functional adenoma that requires surgery. However, for such purpose, biochemical tests can be performed first, after which additional adrenal imaging could be used selectively. The former shows higher diagnostic performance (46) than the latter, which is limited because of the frequently nonspecific image findings (10,12,47,48).

Although we did not include nodules smaller than 10 mm, the possibility that a malignant nodule was present among smaller nodules seems tenuous. According to our per-nodule analysis, no nodule smaller than 15 mm was malignant. Interestingly, the discrepancy between the original CT reports and the retrospective CT image review was most prominent for small nodules 10–15 mm in size, likely because small nodules were more easily overlooked and because the radiologists were already aware from their prior experience that such small nodules are probably clinically unimportant. Importantly, the patients identified in the original CT reports included the two patients with malignant nodules identified in the retrospective CT image review.

The use of virtual noncontrast dual-energy CT images has been suggested as a promising option that could obviate additional noncontrast CT in the work-up of an adrenal nodule (49,50). A recent study (51) has also shown that the diagnostic performance in differentiating adenomas from metastasis could be improved by using the iodine map in addition to virtual noncontrast images. Nevertheless, not all centers are equipped with dual-energy CT scanners, and the efficacy of dual-energy CT with its threshold values for clinical application needs more external validation.

Our study had the following strengths: First, our patient sample was large enough to provide reasonably narrow CIs for the outcome measures with rare event rates. Second, we captured the representative study sample with a strict intention-to-diagnose principle. Our sampling strategy should be distinguished from a convenient sampling of patients with pathologically confirmed gastric cancer or of patients (1719) with pathologically confirmed adrenal nodules. Because of our sampling strategy, our population included 80 patients (1%) who had other malignancies, such as lymphoma or benign ulcers, at the final pathologic analysis.

Our study had limitations. First, this retrospective study took place in one center in a catchment area where gastric cancer is commonly detected at an early stage. The generalizability of our results is uncertain for other regions with different cancer epidemiologic characteristics (52). Further studies that include a greater proportion of patients with advanced gastric cancer are needed. Second, pathologic confirmation was obtained in only a portion of the patients with adrenal nodules. However, the possibility of a missed malignant nodule is likely low, considering that the median follow-up duration (from the earliest to the latest CT examination) in patients whose nodules were adjudicated based on image findings was 53.9 months. Nevertheless, specific diagnoses within the benign nodules may have been inaccurate. For example, a relatively indolent pheochromocytoma with a slow growth rate may have been miscategorized as an adenoma or unclassifiable nodule. Third, the data obtained by using the original CT reports were not entirely prospective in nature, as the specific nodule size was missing in some patients’ reports. Fourth, we did not analyze our results by using demographic factors such as age or sex that are known to be correlated with the prevalence of the adrenal nodules (8). Such factors represent a risk profile that could be implemented in the work-up of adrenal nodules. Fifth, various CT scanners and protocols were used, which may have affected the nodule detection and reference standard adjudication. Last, we did not conduct a cost-effectiveness analysis. A dedicated study weighing the cost of additional imaging studies against the cost of a missed malignant adrenal nodule is needed to formulate more practical guidelines for adrenal nodules.

Although adrenal nodules are detected frequently on staging CT images of patients with otherwise resectable gastric cancer, such nodules rarely turn out to be malignant. Current guidelines should address these incidence rates and provide information related to more selective use of additional imaging for such adrenal nodules.

Disclosures of conflicts of interest: H.Y.K. disclosed no relevant relationships. W.C. disclosed no relevant relationships. Y.J.L. disclosed no relevant relationships. J.H.P. disclosed no relevant relationships. J.C. disclosed no relevant relationships. H.Y.N. disclosed no relevant relationships. H.A. disclosed no relevant relationships. S.I.H. disclosed no relevant relationships. H.J.L. disclosed no relevant relationships. Y.H.K. disclosed no relevant relationships. K.H.L. disclosed no relevant relationships.

Author Contributions

Author contributions: Guarantors of integrity of entire study, W.C., H.Y.N.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, H.Y.K., W.C.; clinical studies, H.Y.K., W.C., Y.J.L., H.Y.N., H.A., S.I.H., H.J.L., Y.H.K., K.H.L.; statistical analysis, H.Y.K., W.C., H.A.; and manuscript editing, H.Y.K., W.C., J.H.P., J.C., H.Y.N., S.I.H., Y.H.K., K.H.L.

Supported in part by the Seoul National University Bundang Hospital Research Fund (grant 09-2020-001).

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Article History

Received: May 11 2021
Revision requested: June 23 2021
Revision received: July 12 2021
Accepted: July 29 2021
Published online: Oct 19 2021
Published in print: Jan 2022