No Repeat Imaging for Most Adrenal Tumors, Call to Change Guidelines

Adrenal tumors found incidentally on imaging tests that are either nonfunctioning or have mild cortisol excess are highly unlikely to grow significantly or to develop into cancer or Cushing syndrome, US and UK researchers have found.

The results of this new meta-analysis therefore suggest that guidelines on the management of these tumors need to be updated to reflect the clinical reality — that is, patients do not need repeated imaging or testing over years of follow-up, say the authors.

Adrenal masses are increasingly being detected incidentally when patients are undergoing ultrasound, MRI, or CT scans, and are found in around 5% of the general population. The majority are nonfunctioning adrenal tumors (NFATs) and benign.

However, around 15% are associated with excess hormone secretion, which, if not properly controlled, can lead to subclinical Cushing syndrome or, as more recently termed, mild autonomous cortisol excess.

Mild autonomous cortisol excess and even NFAT may be associated with increased cardiometabolic risk, and how they are followed-up and managed is the subject of debate.

Conflicting Guidance

The US National Institutes of Health and American Association of Clinical Endocrinologists (AACE) recommend repeated imaging and hormonal assessment for up to 5 years for benign tumors without hormonal hypersecretion.

On the other hand, the more recent European Society of Endocrinology guidelines discourage repeated imaging and assessment, except for the development of overt Cushing syndrome in patients with mild autonomous cortisol excess.

"These considerable differences in recommendations reflect the inadequacy of evidence that informs guidelines," said senior author of the new meta-analysis, Irina Bancos, MD, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, in a press release issued by the University of Birmingham, UK, whose scientists collaborated on the work.

"Therefore, we set out to provide new evidence to determine how many NFAT and mild autonomous cortisol excess tumors increase in size and how often they can cause severe cortisol excess or develop into cancerous tumors," Bancos added.

The study was published online June 25 in Annals of Internal Medicine by lead author Yasir S. Elhassan, MBBS, of University of Birmingham Institute of Metabolism and Systems Research, UK.

In an accompanying editorial, Massimo Terzolo, MD, and Giuseppe Reimondo, MD, PhD, San Luigi Gonzaga Hospital, University of Turin, Italy, praise Elhassan and colleagues for the "careful" way in which the study was conducted.

And they stress that the "most novel finding of the present study is that both patients with nonfunctioning tumors and those with tumors causing autonomous cortisol secretion had at baseline — and developed during follow-up — comorbid conditions and incident cardiovascular events."

Risks of Repeated Imaging Outweigh Any Benefits

Elhassan and colleagues identified 32 studies involving 4000 patients with noncancerous adrenal tumors that were classified as NFAT, mild autonomous cortisol excess, or either one or the other.

The research showed that only 2.5% of adrenal incidentalomas grew to a clinically significant degree over almost 4 years of follow-up. Moreover, none of the patients developed adrenal carcinoma and a tiny proportion developed overt Cushing syndrome.

It was noteworthy, however, that cardiometabolic conditions such as hypertension, dyslipidemia, and type 2 diabetes were highly prevalent at baseline, especially in mild autonomous cortisol excess patients, with new cases diagnosed during follow-up.

Co-author Wiebke Arlt, MD, DSc, director of the Institute of Metabolism and Systems Research, University of Birmingham, said: "Our findings suggest that once patients have been diagnosed with noncancerous NFAT and mild autonomous cortisol excess tumors, they should not undergo repeated follow-up imaging."

This is because the risk of NFAT and mild autonomous cortisol excess tumors "developing into cancer is vanishingly low and repeated imaging would expose patients unnecessarily to radiation," Arlt stresses.

"Repeated hormone testing is also not necessary as mild or absent hormone excess virtually never evolves into severe hormone excess."

AACE Updated Guidance Earlier This Year

Both of these conclusions run counter to current US guidelines and suggest that they should be updated to reflect the clinical reality of adrenal incidentalomas.

In a change that would also impact European guidelines, Arlt said these currently recommend "annual assessment for cortisol excess in patients with mild autonomous cortisol excess; we would suggest this recommendation may need review and possibly revision in light of our findings."

Approached for comment, AACE told Medscape Medical News they agree that the new findings suggest, "when the initial imaging phenotype is consistent with a benign adrenocortical adenoma, there is no indication for subsequent longitudinal imaging re-assessments."

They also concur that "when the initial biochemical phenotype is consistent with nonfunctioning status, or mild autonomous cortisol secretion, there is no strong indication to repeat subsequent biochemical testing."

They point out that, although the 2009 AACE guidelines do indeed recommend annual assessment and repeated imaging, the more recent Disease State Clinical Review, published in February 2019, reflect the more modern clinical understanding of adrenal incidentalomas.

Specifically, they underline that there "is no strong evidence to support repeated longitudinal imaging or hormonal testing in patients with benign and nonfunctioning adrenal adenomas."

They also recommend that patients with mild autonomous cortisol secretions be followed up for cortisol-induced comorbidities.

Consequently, the current study results "further strengthen" these latest recommendations, AACE observes.

Arlt said, "Both patients with NFAT and those with mild autonomous cortisol excess should have clinical check-ups in larger but regular intervals, paying attention to the patients' metabolic health due to their increased risk of hypertension, type 2 diabetes, and cardiovascular disease."

No Adrenal Tumors Transformed Into Adrenocortical Carcinoma

Drilling down into the specifics of the new study, the researchers conducted a comprehensive search of MEDLINE, Embase, Cochrane Database of Systemic Reviews, and Scopus databases for studies published in 1990-2019 that included at least 20 adults with NFAT, mild autonomous cortisol excess, or either, followed for at least 12 months.

Their aim was to better understand the natural history of NFAT and mild autonomous cortisol excess adenomas, and so help guide management.

To assess outcomes such as change in adrenal tumor size, malignant transformation, change in hormone secretion, development of hypertension, obesity, or weight gain, and cardiometabolic outcomes, the team focused on studies with follow-up data for at least 100 patients.

From a total of 139 studies identified, 32 were included in the analysis, of which 17 were retrospective and 15 were prospective.

Overall, the studies included 2873 patients with NFAT, 784 with mild autonomous cortisol excess, and 464 with either condition. The mean age of patients was 60.2 years, 61.5% were women, and the mean duration of follow-up was 50.2 months.

The studies were of moderate to high quality, although there were significant differences in how outcomes were assessed at baseline.

The team found that, across the studies, 6.4% of NFAT or mild autonomous cortisol excess patients experienced any kind of tumor growth.

However, only 2.5% experienced a clinically significant increase in size, defined as at least 10 mm.

Interestingly, larger tumors at least 25 mm in size, were less likely to grow than smaller adenomas, "suggesting that patients with larger tumors were enrolled later in their course of natural history," the researchers observe.

None of the adrenal tumors transformed into adrenocortical carcinoma over a mean follow-up of 49.3 months in 2854 evaluable patients.

And among 2754 patients assessable for changes in hormone production, just six developed overt Cushing syndrome, three developed pheochromocytoma, and none had primary aldosteronism.

Only 4.3% of 2083 patients with NFAT developed mild autonomous cortisol excess over a mean follow-up of 50.3 months.

Meanwhile, mild autonomous cortisol excess resolved in just 18 of 840 patients followed for 49.8 months.

No Imaging or Hormone Tests, but Check for CV Morbidity

It was found, however, that cardiometabolic conditions were highly prevalent at baseline and more frequently reported in mild autonomous cortisol excess than NFAT patients.

Hypertension was reported in 64.0% of patients with mild autonomous cortisol excess and 58.2% of those with NFAT, while 41.0% and 38.8%, respectively, were obese, 34.1% and 33.8% had dyslipidemia, and 28.1% and 14.4% had type 2 diabetes.

Pre-existing cases of both hypertension and dyslipidemia were found to worsen.

Weight gain was more than twice as common in patients with mild autonomous cortisol excess than those with NFAT (21.0% vs 8.7%), and they were much more likely to experience worsening of pre-existing type 2 diabetes (9.2% vs 0.0%).

Over a mean follow-up of 56.3 months, the rate of death from any cause was 11.2%, and was similar between patients with NFAT or mild autonomous cortisol excess.

The main cause of death was cardiovascular mortality, which accounted for 43.2% of deaths and was, again, similar in those with NFAT or mild autonomous cortisol excess.

Findings Support European Guidelines, But More Work Needed

In their editorial, Terzolo and Reimondo say these new findings "robustly confirm" what was previously thought and broadly support the European guidelines.

Speaking to the finding that cardiometabolic conditions and CV events are common among the patients identified, they point out that "to what extent this represents ascertainment bias is presently unknown because patients with diseases are more likely to have imaging tests that may detect an adrenal incidentaloma."

"Further studies are needed to associate results of endocrine work-up with clinical phenotyping and to define patient-centered outcomes," they say.

"We need more evidence to understand what level of cortisol autonomy is tied to clinical consequences. Answering this question is key to developing adequate decision-making strategies concerning the choice between surgery and conservative management for patients with adrenal incidentalomas."

Financial support for the study to individual authors came from the European Commission Horizon 2020 program, National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, a fellowships from the MRC Arthritis UK Centre for Musculoskeletal Ageing Research and Diabetes UK, and to Bancos, a Robert and Elizabeth Strickland Career Development Award, a James A. Ruppe Career Development Award in Endocrinology, and a Catalyst for Advancing in Academics from the Mayo Clinic. Bancos has reported advisory board participation with HRA Pharma. Arlt has reported a patent held by University of Birmingham Enterprises for a diagnostic test. Terzolo has reported receiving grants from HRA Pharma and Novartis, and personal fees from HRA Pharma.

Ann Intern Med. Published online June 25, 2019. Abstract, Editorial

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