Most Bilateral Adrenal Lesions Are Benign and Concordant, but Asynchronous Presentation Signals Higher Malignancy Risk

Highlight

In this large tertiary-center cohort of 1,035 adults with bilateral adrenal masses, 85% of cases had concordant etiologies, most commonly bilateral benign cortical lesions.

Discordant etiologies were less common but clinically important, spanning benign, malignant, and indeterminate lesions in near-equal proportions.

Asynchronous presentation occurred in 16% of patients and was associated with substantially higher rates of discordance and malignancy than synchronous disease.

Among asynchronous cases, earlier development of the contralateral lesion and larger tumor size independently increased the likelihood of malignancy or pheochromocytoma.

Background

Bilateral adrenal lesions present a recurring diagnostic challenge in endocrine practice. Although unilateral adrenal incidentalomas are common and increasingly detected through cross-sectional imaging, bilateral adrenal masses are less straightforward because the differential diagnosis is broader, the probability of systemic disease is higher, and the clinical implications of lesion symmetry are not always obvious. Clinicians must determine whether both adrenal lesions represent the same underlying process, whether a new lesion on the opposite side changes the diagnostic framework, and how urgently malignancy or catecholamine-secreting tumors should be excluded.

The spectrum of bilateral adrenal disease is wide. Benign cortical adenomas and nodular hyperplasia are common, but bilateral disease can also reflect metastatic spread, primary adrenal malignancy, infiltrative or infectious disorders, congenital or acquired hyperplasia, and bilateral pheochromocytoma, particularly in hereditary syndromes. In many patients, imaging findings alone are insufficient to distinguish these categories. Biochemical testing, prior cancer history, lesion growth behavior, and timing of appearance may all modify the pretest probability of clinically dangerous disease.

Current adrenal incidentaloma guidance emphasizes hormonal evaluation, careful imaging characterization, and individualized follow-up, but evidence specifically addressing bilateral lesions remains comparatively limited. One unresolved issue is etiologic concordance: if one adrenal lesion appears benign, how often is the lesion on the opposite side driven by the same process? Another is temporal presentation: does a contralateral lesion discovered months or years later indicate a different biology than bilateral lesions found simultaneously? The study by Lu and colleagues addresses these practical gaps using a large retrospective cohort from a tertiary referral center.

Study Design

This was a retrospective cohort study conducted from 2010 to 2025 at a tertiary referral center and included adults with bilateral adrenal masses. The investigators examined the etiologic spectrum of bilateral adrenal lesions and classified presentations along two clinically intuitive dimensions: concordance versus discordance of etiology, and synchronous versus asynchronous timing of presentation.

The main outcomes were lesion etiology, frequency of concordant and discordant bilateral disease, synchronous versus asynchronous detection, interval to development of a contralateral lesion, and predictors of discordant or malignant/pheochromocytoma contralateral lesions. The key inferential analysis focused particularly on patients with asynchronous disease, in whom the emergence of a lesion in the opposite adrenal gland may carry greater diagnostic uncertainty.

The cohort comprised 1,035 patients with a median age of 59.6 years, and 51% were women. This is a relatively large sample for a study focused specifically on bilateral adrenal pathology, an area where many previous reports have been smaller or enriched for selected disease subtypes.

Key Findings

Overall etiologic pattern: concordance predominates

The central finding is that most bilateral adrenal masses are etiologically concordant. Overall, 85% of patients had concordant etiologies, while 15% had discordant disease. This is clinically reassuring. In routine practice, bilateral adrenal lesions often raise concern that one or both masses may represent occult malignancy or a syndromic process; however, the data suggest that the default pattern is usually the same pathologic process affecting both glands.

Among concordant cases, bilateral benign cortical lesions dominated, accounting for 76%. This aligns with everyday endocrine imaging experience, in which adenomas and related benign cortical processes account for most incidentally discovered adrenal masses. For clinicians, this finding supports the idea that when both lesions share benign imaging features and the biochemical evaluation is not concerning, bilateral disease alone should not automatically imply high oncologic risk.

Discordant disease is uncommon but heterogeneous

The 15% of patients with discordant etiologies deserve disproportionate attention because this subgroup was not defined by one alternate pathway, but by marked heterogeneity. In discordant cases, 35% were benign, 31% malignant, and 34% indeterminate. In other words, once the bilateral lesions are not etiologically matched, the probability of facing a non-benign or unresolved diagnosis rises considerably.

This observation is important for imaging interpretation and clinical reasoning. It argues against overly simplistic assumptions such as “bilateral means benign hyperplasia” or “a known adenoma on one side explains the lesion on the other.” Instead, each adrenal lesion still requires lesion-specific assessment, especially when imaging characteristics differ, when one lesion grows more rapidly, or when biochemical findings are discordant with a presumed benign explanation.

Synchronous presentation is most common, but asynchronous disease is a higher-risk pattern

Most patients presented synchronously, meaning both adrenal lesions were identified at the same time or in the same diagnostic episode. Synchronous presentation occurred in 84% of the cohort, whereas 16% developed asynchronous disease. The median interval to identification of the contralateral lesion in asynchronous cases was 45 months, with an interquartile range of 15 to 87 months, underscoring that contralateral disease may emerge years after the initial lesion.

Timing mattered clinically. Asynchronous presentation was associated with a higher rate of discordant etiologies than synchronous presentation: 23% versus 13%, respectively, with P=0.001. This suggests that lesions appearing at different times are less likely to represent a single stable bilateral benign process and more likely to reflect distinct biology.

Asynchronous disease was also associated with a greater prevalence of malignant lesions. Bilateral malignant disease occurred in 17% of asynchronous cases versus 7% of synchronous cases, and discordant malignant disease occurred in 8% versus 4%, with an overall P value of less than 0.001. These are clinically meaningful differences. They indicate that the discovery of a new contralateral adrenal mass during follow-up should prompt careful reassessment rather than passive extension of the original diagnosis.

Predictors within asynchronous disease: early contralateral appearance and larger size matter

The most practice-relevant analysis focused on patients with asynchronous bilateral lesions. In this subgroup, a shorter interval to development of the contralateral lesion, defined as less than 2 years versus at least 5 years, was independently associated with malignant or pheochromocytoma etiology. The adjusted odds ratio was 2.63, with a 95% confidence interval of 1.01 to 6.85.

Larger tumor size was also independently associated with malignant or pheochromocytoma etiology, with an adjusted odds ratio of 1.06 per mm and a 95% confidence interval of 1.02 to 1.09. Although a 6% increase in odds per millimeter may appear modest, the effect becomes substantial across a clinically relevant size range. Over a difference of 10 mm, the cumulative increase in odds is meaningful and consistent with long-standing adrenal oncology principles linking lesion size with malignant potential.

These findings provide a practical framework. Among patients already known to have a unilateral adrenal lesion, a contralateral lesion that appears relatively early and is larger should raise suspicion for pheochromocytoma or malignant disease, and should trigger prompt biochemical workup, careful imaging review, and individualized staging or surveillance planning.

Clinical Interpretation

This study offers a useful recalibration of risk. The main message is not that bilateral adrenal masses are dangerous by default, but that risk is not evenly distributed across all bilateral presentations. Most bilateral lesions are benign and concordant. The higher-risk phenotype is defined by discordance and, especially, by asynchronous development.

From a bedside perspective, the study suggests a tiered approach. First, when bilateral lesions are discovered synchronously and have comparable benign cortical imaging characteristics, the working diagnosis of concordant benign cortical disease will often be correct, provided standard hormonal evaluation does not suggest autonomous secretion or catecholamine excess. Second, if the lesions differ radiologically, biochemically, or clinically, one should resist assuming common etiology. Third, in patients with prior unilateral disease, a new contralateral lesion should be treated as a potentially new event rather than simply the delayed completion of a benign bilateral pattern.

The increased association with pheochromocytoma in the asynchronous subgroup is also notable. Bilateral pheochromocytoma may occur in hereditary tumor syndromes, but in routine clinical pathways, the clue may be a contralateral lesion appearing over time. This reinforces the need to maintain guideline-concordant biochemical exclusion of catecholamine-secreting tumors before biopsy or surgery is considered.

How These Findings Fit With Existing Guidance

Recent European Society of Endocrinology guidance on adrenal incidentalomas emphasizes that bilateral adrenal incidentalomas should undergo the same clinical, radiologic, and hormonal evaluation as unilateral adrenal masses, while also considering bilateral-specific causes such as hyperplasia, metastases, infiltrative disease, and hereditary syndromes. The present study adds granularity by showing that temporal pattern and etiologic concordance can refine that evaluation.

The results are also consistent with broader adrenal oncology principles. A history of extra-adrenal malignancy, atypical imaging features, interval growth, and larger lesion size remain classic warning signs for malignant adrenal involvement. Lu and colleagues extend this framework by demonstrating that the timing of contralateral lesion emergence itself carries signal. In effect, time becomes a diagnostic variable, not merely a surveillance detail.

Strengths and Limitations

The study’s strengths include its large sample size, explicit classification of bilateral lesions by concordance and synchronicity, and focus on clinically useful predictors. The inclusion of over 1,000 patients from a tertiary center makes this one of the more substantial analyses specifically addressing bilateral adrenal masses.

Several limitations should temper interpretation. First, as a retrospective cohort, the study is vulnerable to selection bias, referral bias, and incomplete standardization of diagnostic workup. A tertiary referral population may overrepresent complex, atypical, or higher-risk cases relative to general practice, which can influence both etiologic prevalence and the apparent value of certain predictors. Second, the abstract does not provide detailed definitions for all etiologic categories, adjudication methods, biochemical protocols, imaging criteria, or surgical/pathologic confirmation rates. Third, the study reports associations rather than causal mechanisms. For example, earlier appearance of a contralateral lesion may mark aggressive biology, occult systemic disease, or more intensive surveillance rather than an independent biologic driver. Fourth, the odds ratio for shorter interval to contralateral lesion, although significant, has a wide confidence interval, suggesting some uncertainty in the exact magnitude of effect.

Even with these limitations, the overall signal is coherent and clinically plausible. The study does not overturn adrenal incidentaloma management, but it sharpens risk stratification within the bilateral subgroup.

Practical Implications for Clinicians

Several actionable points emerge. Bilateral adrenal lesions should not automatically be managed as high-risk solely because they are bilateral. Most are benign and concordant. However, clinicians should actively identify features that move a patient out of that lower-risk category.

Those features include asynchronous presentation, marked differences in lesion appearance between glands, rapid contralateral development, larger size, suspicious imaging phenotype, and biochemical or clinical evidence suggestive of pheochromocytoma or adrenal malignancy. In such settings, follow-up should be more deliberate and multidisciplinary, often involving endocrinology, radiology, endocrine surgery, and oncology.

For surveillance conversations, the median 45-month interval to contralateral lesion in asynchronous disease is a reminder that clinically relevant bilateralization may occur late. This does not imply that prolonged routine imaging is necessary for all patients, but it does support individualized follow-up in patients with atypical lesions or evolving risk factors.

The study may also help avoid over- and under-treatment. It can reassure clinicians and patients when synchronous bilateral lesions are radiologically typical of benign cortical disease, while also identifying scenarios in which a newly discovered opposite-side lesion should not be dismissed.

Conclusion

Lu and colleagues provide important evidence that bilateral adrenal masses are usually benign and etiologically concordant, with bilateral benign cortical lesions accounting for most cases. The clinically consequential minority are those with discordant etiologies and, particularly, those with asynchronous presentation. In these patients, the risks of malignancy and pheochromocytoma rise meaningfully.

The most useful practical signals are timing and size. A contralateral lesion that appears early after the first adrenal mass and is larger at presentation warrants heightened suspicion and more comprehensive evaluation. For endocrinologists, internists, oncologists, radiologists, and surgeons, this study supports a more nuanced framework for bilateral adrenal disease: reassuring in the majority, but appropriately vigilant in asynchronous or discordant patterns.

Funding and ClinicalTrials.gov

Funding information was not provided in the abstract. No ClinicalTrials.gov registration number is reported, which is expected for many retrospective observational cohort studies.

References

Lu H, Aggarwal E, Hodhod AY, Achenbach SJ, Atkinson EJ, Yu K, Powell CM, Bancos I. Presentation and Clinical Patterns of Bilateral Adrenal Lesions: A Retrospective Cohort Study. The Journal of Clinical Endocrinology and Metabolism. 2026-05-12. PMID: 42117556.

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