Adrenocortical carcinoma classified as benign: the limitations of washout values

Background

The widespread use of cross-sectional imaging has led to increased detection rates of adrenal masses. They are found in 2% of general population rising to over 7% of those aged over 70 years (1). Adrenal incidentalomas are mostly benign, but it is crucial to exclude malignancy and hormonally active lesions. Prevalence of adrenocortical carcinoma is 0.4–4% among adrenal incidentalomas (2). Following the latest European Society of Endocrinology guidelines regarding the management of adrenal incidentalomas (2), we wish to highlight our experience of a case of non-functioning adrenal incidentaloma, which had initially benign appearances based on washout characteristics, but then re-presented 2 years later as an adrenocortical carcinoma.

Case presentation

A 29-year-old female presented in 2020 with a history of weight loss and altered bowel habit. She was referred to endocrinology after a CT scan discovered a 3.4 cm left adrenal nodule, which was reported as benign based on washout values. Initial biochemistry work-up was normal (Table 1). She has a history of asthma but no history of hypertension, diabetes or osteoporosis. She reported no specific symptoms. She re-presented 2 years later with abdominal discomfort and left upper quadrant mass. She had no clinical features of steroid, catecholamine or androgen excess. A repeat CT showed an increase in size of adrenal lesion 17 × 11 cm.

Investigations

The initial biochemical work-up found potassium level 4.6 mmol/L (3.5–5.3 mmol/L), normal overnight dexamethasone suppression test with cortisol 38 nmol/L (<50 nmol/L) and normal plasma metanephrines. Urinary steroid profile was not performed at this time due to benign radiological findings.

CT adrenal showed a 3.4 cm focal lesion in the left adrenal gland. The lesion was homogenous with no cystic, haemorrhagic, necrotic or calcific components. The average attenuation was 38 HU and absolute washout of 72%. Given the washout characteristics, it was reported as representative of a benign adenoma (Fig. 1A and B). Retrospectively, we calculated the relative washout to be 39%.

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CT images of initial presentation and 2 years later. (A) Initial pre-contrast CT showing adrenal lesion of 38 HU. (B) Initial post-contrast CT of a homogenous adrenal lesion with absolute washout of 72%. (C) Coronal view of the large left adrenal lesion with central necrosis. (D) 11.6 × 16.5 cm well-defined, heterogeneously enhancing left adrenal lesion with central necrosis suspicious of adrenal cancer.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 2; 10.1530/EDM-24-0022

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Two years later, a repeat CT showed significant increase in size of the adrenal lesion (17 × 11 cm). The lesion is heterogeneous with necrotic components and large abnormal feeding vessels, which was suspicious of an adrenocortical cancer (Fig. 1C and D). The hormonal work-up, summarised in Table 1, showed non-suppressed cortisol 148 nmol/L (<50 nmol/L) on 1 mg overnight dexamethasone suppression test, raised androstenedione 13.5 nmol/L (0–5.5 nmol/L) and dehydroepiandrosterone (DHEAS) 24.1 μmol/L (1.2–10.3 μmol/L). The ACTH was normal at 31 ng/L (7–56 ng/L). The urinary steroid profile showed significantly raised androgen and intermediate metabolites. Urine metadrenalines, aldosterone and renin levels were normal.

Treatment, outcome and follow-up

She underwent left open adrenalectomy with left nephrectomy and splenectomy. Pathology reported a 22 cm adrenal cortical carcinoma, predominantly necrotic, with only few viable areas. Overall Ki67 was greater than 10%. The Weiss score was 5 (nuclear pleomorphism, diffuse architecture, necrosis, mitotic rate and atypical mitoses). Subsequently she was commenced on mitotane.

Discussion

Following this case, we reviewed our prospectively collected adrenal incidentaloma database for patients seen from April 2017 to December 2022, who attended our nurse-led adrenal incidentaloma pathway for biochemistry investigations. Patients were then reviewed in the medical clinic with the results. We excluded patients who refused investigations, incomplete investigations or inaccurate diagnosis.

There were 516 patients reviewed, of which 196 were males and 320 females. A total of 57 patients had no size mentioned on CT scans and 12 patients with lesions <10 mm. These patients underwent the nurse-led pathway due to lack of clarity on initial imaging in terms of size and characteristics. The mean age was 63.9 years (range: 19–90 years).

The mean size of the lesion was 24 mm (range: 5–128 mm), standard deviation 14.5 and median 20 mm (interquartile range 13 mm). A total of 377 (73%) patients had HU reported. Of these, 260 patients (69%) had lesions <10 HU, 37 (9.8%) with 10–20 HU and 80 (21.2%) with >20 HU. There were 139 patients who had no HU reported and they were categorised into benign (n = 27), low density or attenuation (n = 23), fat-containing (n = 30), metastasis (n = 1), indeterminate (n = 14), others (n = 3) or no information (n = 41). The three patients reported as ‘others’ include a phaeochromocytoma, adrenal haemorrhage and no nodule on dedicated adrenal CT.

From our database, there were 11 patients under the age of 40 (representing around 2% of all patients assessed). Their adrenal incidentaloma measured 0.8–3.4 cm. Seven patients had lesions <10 HU or lesions reported as fat-containing or low density. One patient had an indeterminate 0.8 cm lesion, which was discussed in MDT and thought to be benign. Three patients had HU >10, of which one is due to metastases, one adrenal haemorrhage and one adrenal cancer.

In the previous European guidelines on adrenal incidentaloma, it was suggested calculating washout characteristics using a standard protocol if lesion is above 10 HU (3, 4). Schloetelburg et al. reported that 22% of all potentially malignant lesions showed absolute washout values above 60% (5). All potentially malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In the most relevant subgroup, the established thresholds of 60% for absolute washout and 40% for relative washout misclassified 35.9 and 35.2% of the masses, respectively. They have shown that for absolute washout threshold of >60%, the positive predictive value was 92.2. However, the negative predictive value was only 34.2. This suggests that adrenal washout on CT may have limited value in the assessment of indeterminate nodules, especially in patients with a nodule >10 HU without known malignancy (5). Similarly, Corwin et al. studied 299 patients without known malignancy who underwent washout CT. Absolute washout of >60% was shown in 73.3% of pathologically confirmed adenomas. However, 20% of malignant nodules also showed washout of 60% or more (6). Therefore, using high washout values as an indicator of a benign lesion is not sufficiently specific, meaning malignant lesions cannot be completely excluded, particularly if the pre-contrast density is high.

With reference to the previous ESE adrenal incidentaloma guidelines (2016), an absolute washout >60% would be considered benign, as in this patient’s initial scan (3). With the new version of guideline published in 2023, CT with relative washout >58% suggests a benign mass, although with a need to judge with caution as cut off based on a single study (2). Given the HU on the initial report, this patient would have proceeded to further imaging or immediate surgery following the latest published guideline. Dinnes et al. reported insufficient evidence for the diagnostic value of individual imaging techniques in distinguishing benign from malignant adrenal lesions. While masses with ≤10 HU are unlikely to be malignant, a HU value above 10 may or may not represent malignancy. Possible explanations included variability in the lipid content of adenomas, tissue heterogeneity, small size of metastatic lesions or differences in selecting regions of interest for HU measurement. The threshold chosen has been identified from studies with limited follow-up. Moreover, cases with adrenal cancers formed only a small proportion of the cohort studied and therefore the negative predictive value for absence of malignant disease is likely an over-estimate (7). This case highlights that washout values can be misleading and clinicians need to be aware of this when considering follow-up imaging.

The estimated risk of developing adrenal malignancy during follow-up from a systematic review was 0.2% (8). Two cohort studies included in the systematic review found two malignancies (non-Hodgkin lymphoma and renal cancer metastases). It is unclear if these patients had benign features on initial imaging (9, 10).

The number of patients under the age of 40 with adrenal incidentalomas in our group is small. As adrenal incidentalomas in patients <40 years of age have higher likelihood of malignancy, we proposed locally that these patients should have interval imaging, if pre-contrast density is >10 HU, instead of additional imaging such as washout CT. This recommendation would impact less than 1% of our patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work report.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

P S Yap was involved in the follow-up of patient, design, data collection and analysis, writing of initial draft, literature search and editing of the final manuscript. S Philip was involved in study design, data analysis, literature review, editing of images and the final manuscript. A J Graveling contributed to the patient’s management, study design and editing of the final manuscript. D McAteer reviewed and selected radiological images and edited the final manuscript. S Aspinall performed the surgical resection and participated in editing of the manuscript. P Abraham was responsible for the management and treatment of patient, study design and editing of the final manuscript.