OXFORD
ENDOCRINE SOCIETY
Is adrenal adenoma to carcinoma transformation possible ?- Illustrative cases and literature review
Sophie Howarth @ 1,2, James MacFarlane @ 1,2, Lisa Yang2, Ines Harper3,4, Ashley Shaw3, Yasir S. Elhassan5,6, Vasilis Kosmoliaptsis7, Mark Gurnell1,2, Cristina L. Ronchi ID 5,6, and Ruth T. Casey (D 1,2,8
1Cambridge Endocrine Molecular Imaging Group, Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
2 Department of Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
3 Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
4 Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
5Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham B15 2WB, UK 6Department of Endocrinology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2WB, UK 7Department of Surgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 OQQ, UK 8 Department of Genetics, University of Cambridge, Cambridge CB2 0QQ, UK
Correspondence: Ruth T. Casey, MBBCh, BAO, PhD, Department of Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK. Email: rc674@medschl.cam.ac.uk.
Abstract
Context A minority of adrenocortical carcinomas (ACC) demonstrate indolent growth but can usually be identified by radiological characteristics such as inhomogeneity or high unenhanced density. However, cases of ACC developing from a lesion with benign radiological features at baseline and histopathological reports of ACC embedded within an adrenal adenoma have emerged. The adenoma to carcinoma transition in the adrenal gland may be a possible, albeit rare, phenomenon.
Case Descriptions We present 2 cases from 2 tertiary centers in the United Kingdom who were diagnosed with an adrenal adenoma and showed stable radiological characteristics over 14 years and 11 years, respectively, prior to a rapid enlargement of the lesion and diagnosis with ACC. We review the existing literature and describe 4 additional cases who met radiological criteria for an adrenal adenoma and demonstrated prolonged lesion stability (>5 years) on serial imaging prior to a subsequent diagnosis of ACC. We also identify 4 case reports of patients with radiologically indeterminate adrenal nodules at baseline who demonstrated prolonged size stability for up to 10 years prior to an accelerated growth phase and diagnosis with ACC. There was no significant difference in the average time to ACC diagnosis seen in those with benign radiological features at baseline (10.5 years, n = 6) and those with radiologically indeterminate nodules at baseline (8.75 years, n = 4, P = . 39).
Conclusion Adrenal lesions with baseline benign radiological characteristics can very rarely transpire to be ACC. Prolonged dimensional stability cannot be considered a reassuring feature in isolation when assessing radiologically indeterminate adrenal lesions.
Keywords adrenocortical carcinoma, adrenal adenoma, adrenal incidentaloma
Abbreviations: ACC, adrenocortical carcinoma; CT, computed tomography; HU, Hounsfield unit; MACS, mild autonomous cortisol secretion; MDT, multidisciplinary team; MRI, magnetic resonance imaging; OR, odds ratio; PET, positron emission tomography; RR, reference range.
The adenoma-carcinoma sequence, in which carcinogenesis results from the progressive accumulation of driver muta- tions, has been demonstrated in several cancer types and is perhaps best exemplified by colorectal cancer, in which vil- lous and tubulovillous adenomas show a particular propen- sity to progress to overt malignancy (1). Although it is
conceivable that a similar stepwise progression could occur in the adrenal cortex, to date there is little evidence to sup- port such a pathway. Indeed, contemporary clinical practice guiding the management of adrenal lesions relies on the principle that adrenocortical adenomas remain benign and do not transform to malignant disease (2, 3).
Incidental adrenal lesions (“incidentalomas”) detected on cross-sectional computed tomography (CT) imaging have a prevalence between 1.05% and 8.7% depending on the age of the population (4). Benign, nonfunctioning adenomatous or hy- perplastic lesions account for 40% to 70% of all incidentalomas (5), and autopsy studies show that adrenal adenomas are com- mon in the wider population with a median frequency of 3% (4). In contrast, adrenocortical carcinoma (ACC) is rare, affecting between 0.5 and 2 per million population per year (6), and diag- nosed in 0.4% to 4% of all patients with adrenal incidentalomas (5). ACC is an aggressive cancer with a variable prognosis that is substantially poorer in the presence of metastatic disease (7). Complete surgical resection provides the only means of cure and therefore early identification of malignant adrenal lesions is critical (7). However, this need must be balanced against the opportunity costs associated with investigating and surveilling adrenal incidentalomas in resource-constrained health care sys- tems. Consequently, accurately identifying adrenal lesions that do not require further investigation or follow-up is important. ☒
In a large tertiary center study of adrenal incidentalomas, im- portant predictors of malignancy were an unenhanced CT at- tenuation value of >20 Hounsfield units (HU) (odds ratio [OR], 28.40), androgen excess (OR, 27.67), detection during general cancer surveillance (OR, 11.34), size >4 cm (OR, 6.11), and male sex (OR, 3.06) (8). A threshold of >10 HU for unenhanced at- tenuation on CT has been reported in a meta-analysis of adrenal incidentalomas to have a sensitivity of 100% for the detection of malignancy (9). In contrast, imaging features that favor a benign adrenal lesion include homogeneity, with unenhanced attenu- ation <10 HU on CT, absent radioligand uptake or uptake less than the liver on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) CT (PET-CT), loss of signal intensity (“signal drop out”) on out-of-phase sequences during chemical shift magnetic resonance imaging (MRI), and a relative washout of >58% on delayed contrast-enhanced CT (5). Furthermore, the presence of a high proportion of macroscopic fat (typically >50%) within an adrenal lesion is commonly used to support a radiological diagnosis of a benign myelolipoma (10).
European Society of Endocrinology adrenal incidentaloma guidelines recommend that in a patient with a homogenous, nonfunctioning adrenal lesion <4 cm in size, and unenhanced CT attenuation ≤10 HU, no further investigation or follow-up is required. For homogeneous nonfunctioning adrenal lesions <4 cm size, but with attenuation values on unenhanced CT be- tween 11 and 20 HU, either immediate further characterization with a second imaging modality (eg, chemical shift MRI) or inter- val imaging at 12 months is recommended. Early multidisciplin- ary team (MDT) review is recommended for adrenal lesions with any of the following characteristics: (1) unenhanced CT attenu- ation of 11 to 20 HU with a size >4 cm; (2) homogeneous lesions <4 cm with unenhanced CT attenuation >20 HU; or (3) heteroge- neous lesions, regardless of size. In these scenarios, expert dis- cussion helps guide decisions regarding further investigation and management. Adrenal lesions falling outside of these criteria should be considered for early surgical intervention. In contrast, adrenal lesions <1 cm in size, and without other concerning fea- tures, typically do not require investigation or follow-up (5).
A small number of case reports have recently described ACC de- veloping several years after the diagnosis of an ipsilateral adrenal adenoma (11-14). In addition, cases of ACC arising within a
preexisting adrenal adenoma have been reported (15-17). Here, we present 2 further cases identified through review of adrenal multidisciplinary team referrals at 2 tertiary centers in the United Kingdom, in which patients appeared to develop ACC several years after the initial detection of an adrenal lesion. Both patients met recommended criteria for discharge, based on low unenhanced CT attenuation, prolonged radiological stability over time, and re- assuring features on an additional imaging modality. These cases raise the possibility-albeit rare-of progression from adrenal aden- oma to carcinoma and underscore the need for improved bio- markers to inform long-term follow-up strategies in selected patients with incidentally discovered adrenal lesions.
Methods
Cases were selected from a retrospective review of adrenal MDT records from 2021 through 2025 at Cambridge University Hospital NHS Foundation Trust (~240 patients a year reviewed) and University Hospitals Birmingham NHS Foundation Trust (~260 patients a year reviewed). Patients with a diagnosis of ACC were included if they had been: (1) reviewed at an adrenal MDT and (2) had previous imaging suggestive of an adrenal ad- enoma (lesion size <4 cm, unenhanced density ≤20 HU, lesion stability over time). Two cases were identified for detailed de- scription, with ACC confirmed by either histopathology or by mo- lecular imaging methods (Table 1). We excluded cases with prior incomplete radiological characterization and cases where the baseline unenhanced density was >20 HU.
A literature review was performed on PubMed using the terms “adrenocortical cancer,” “ACC,” and “adenoma.” Case reports were included if they had serial adrenal imaging prior to diagno- sis of ACC demonstrating prolonged dimensional stability. Case reports were categorized into those where initial radiological characterization demonstrated benign radiological features (le- sion size <4 cm and unenhanced CT attenuation ≤20 HU and di- mensional stability >1 year) (n = 4, Table 2) and those with either incompletely described or indeterminate nodules (lesion size <4 cm with unenhanced density >20 HU, but with dimensional stability >1 year) (n = 4, Table 3). These subcategories were in- cluded to investigate differences in the rate of growth between lesions that had baseline characteristics suggestive of a lipid-rich adenoma vs those with indeterminate radiological characteris- tics. Cases from case series were also included during the search.
Case 1
A man in his 60s was referred to the adrenal service for further assessment of a 40-mm left adrenal lesion seen on a CT pulmon- ary angiogram. Twelve years earlier, a 30-mm left adrenal lesion had been detected incidentally on a contrast-enhanced CT scan of the abdomen and pelvis, which was performed during an ad- mission with meningitis. At the time, the lesion was considered most consistent with an adrenal adenoma, but no further clinical or radiological characterization was undertaken. Four years later (8 years prior to referral to the adrenal service), the lesion was formally characterized as a homogenous 37-mm nonfunctioning adenoma with unenhanced density of -10 HU and normal bio- chemical assessment (Fig. 1).
| Demographics | Identification and monitoring of adrenal adenoma | Apparent transformation to ACC | Treatment and Outcome | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case Age at initial nodule detection | Sex | Other medical comorbidities | Initial imaging | Initial biochemical assessment | Time to ACC diagnosis | Interval imaging | Imaging at diagnosis of ACC | Hormone secretion | Histopathology | Metastases | |
| 1 57 | M COPD, T2DM, OSA, Obesity | CT TAP with contrast: 30 mm | Nonfunctioning | 14 years | CT TAP at year 4: 37 mm, unenhanced HU -10 CT aortogram at year 5: 40 mm, unenhanced HU 4 MRI adrenal at years 12 and 14: stable size, signal drop out on chemical shift imaging | [1]C]MTO PET-CT: 79 mm x 60 mm metomidate-avid left adrenal mass with metomidate-avid lung and nodal metastases | Mild | N/A | Lung, mediastinal and hilar nodes | Best supportive care, died 2 months following diagnosis. | |
| homogeneous left | autonomous | ||||||||||
| adrenal nodule. Initial | cortisol | ||||||||||
| unenhanced HU not available. | secretion | ||||||||||
| 2 64 | F | Asthma, HTN, Follicular | CT colon with contrast: | Not performed | 11 years | Annual contrast-enhanced CT | [18F]CETO PET-CT: 96 mm CETO-avid heterogeneous right | Mild | 100 mm adrenocortical carcinoma; R0 resection; | None | [18F]CETO PET-CT avid pulmonary metastases at 16 months postoperatively, commenced on mitotane. |
| 23 mm × 28 mm right | scans showing stable | autonomous | |||||||||
| lymphoma | adrenal nodule. Initial | adrenal nodule [18F]FDG-PET at year 4: unenhanced HU 19.6, no tracer uptake [18F]FDG-PET at year 8: no | adrenal lesion | cortisol secretion | LWB-2 major and 2 minor criteria; Ki67 12%. | ||||||
| unenhanced HU not available. | |||||||||||
| tracer uptake | |||||||||||
Abbreviations: COPD, chronic obstructive pulmonary disease; CT TAP, computed tomography scan of thorax, abdomen, and pelvis; [11C]MTO-PET, [11C]metomidate positron emission tomography; [18F]CETO PET, para-chloro-2-[18F]fluoroethyletomidate positron emission tomography; [18F]FDG-PET, [18F]fluorodeoxyglucose positron emission tomography; HTN, hypertension; HU, Hounsfield units; LWB, Linn-Weiss-Bisceglia criteria; OSA, obstructive sleep apnea; T2DM, type 2 diabetes.
Following referral to the adrenal service, an MRI scan was per- formed which demonstrated a 40-mm left adrenal lesion with signal loss on chemical shift imaging (Fig. 2). There were no overt clinical features of hypercortisolism, but biochemical assessment was consistent with mild autonomous cortisol secretion (MACS) with a nonsuppressed overnight dexamethasone suppression test of 81 nmol/L (reference range (RR) < 50 nmol/L) and elevated late night salivary cortisol levels of 4.5 nmol/L and 4.6 nmol/L (RR < 4.3 nmol/L). In view of the lesion size and possible MACS, contin- ued surveillance was advised and included a repeat MRI scan 2 years later that showed stable size (42 mm) and continued signal dropout in keeping with an adenoma. Given the patient’s associ- ated comorbidities, the adrenal MDT felt he would be a high-risk surgical candidate, and he was discharged with advice for cardio- vascular risk optimization. At this stage, his left adrenal lesion had been stable for 14 years (Table 1).
However, 8 months later, a CT pulmonary angiogram performed for dyspnea showed multiple scattered lung nodules and enlarged thoracic nodes concerning for metastatic malignancy. In addition, the left adrenal lesion had increased in size from 42 x 35 mm to 52 × 49 mm (Panel B, Fig. 1). [18F]FDG PET-CT showed the left ad- renal lesion was now heterogeneous, and both the adrenal and pul- monary lesions demonstrated high [18F]FDG uptake. [11C]metomidate PET-CT (using the radioligand [11C]metomidate ([11C]MTO), which shows highly selective binding to the adrenocort- ical enzymes CYP11B1 and CYP11B2) was performed 3 months later and revealed a 79-mm [11C]MTO-avid left adrenal lesion, with high tracer uptake also seen in multiple pulmonary and thoracic nodal metastases, consistent with metastatic ACC (Fig. 1). Following multi- disciplinary team discussion, a decision was made to pursue best supportive care in view of the patient’s poor performance status. He died 2 months later.
Case 2
A woman in her 70s with a background of follicular lymphoma was referred to the adrenal service after a 37-mm right adrenal lesion was identified on contrast-enhanced CT colonography performed for altered bowel habit. The lesion had first been noted 11 years earlier on a contrast-enhanced CT scan of the abdomen. Over the subsequent 11 years, annual contrast-enhanced CT scans per- formed as part of her lymphoma surveillance program demon- strated slow interval growth of the adrenal lesion, with an overall increase in size of 9 mm (ie, <1 mm per year). In addition, 1 [18F]FDG PET-CT scans performed at years 4 and 8 had shown very low [18F]FDG uptake within the right adrenal lesion, which had also been found to have an attenuation value of 19.6 HU on unenhanced CT at the time of the first [18F]FDG scan. Taken to- gether, these findings were considered most consistent with an adrenal adenoma.
On review in the adrenal service, MACS was suspected with the finding of a serum cortisol of 109 nmol/L (RR < 50 nmol/L) fol- lowing a 1-mg overnight dexamethasone suppression test (with adequate serum dexamethasone level of 6.1 nmol/L). Two late night salivary cortisol tests and 24-hour urinary free cortisol measurements were unremarkable. However, at the time of re- ferral, the 37-mm right adrenal lesion now exhibited an attenu- ation value of 33 HU on unenhanced CT. In view of the <1-mm/year growth over an 11-year period and very low level
| Demographics | Identification and monitoring of adrenal adenoma | Apparent transformation to ACC | Treatment and outcome | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case | Age at initial nodule detection | Sex Other medical comorbidities | Initial imaging | Initial biochemical assessment | Time to ACC diagnosis | Interval imaging | Imaging at diagnosis of ACC | Hormone secretion | Histopathology | Metastases at diagnosis | |
| Angelousi | 64 | M HTN | 30-mm | Nonfunctioning | 13 years | Yearly CT for 3 | CT AP at year 13: | Cortisol, | Metastatic ACC; | Liver, lung | Treated with mitotane |
| et al 2024 | homogenous | years, then | 120 mm | androgens | Ki67 70%, Weiss | and etoposide, | |||||
| (11) Cristofolini et al 2024 (12) | 73 | M Not reported | left adrenal lesion, HU <10 14-mm left adrenal lesion, HU 20 | Nonfunctioning | 5 years | every 2 years. Lost to follow up for 4 years. CT scan at year 11 showing 30 mm lesion but 24 HU. 6 monthly CT scans for 2 years. | heterogeneous left adrenal lesion CT AP at year 5: 145 mm left adrenal lesion | None | score not reported (from liver lesion biopsy) ACC, Ki67 5%; Weiss score 7 | None | doxorubicin and cisplatin with partial response. Alive at 8 months after diagnosis. Left adrenalectomy and nephrectomy. No adjuvant therapy. No recurrence at 3 months postoperatively. |
| Parry et al 2024 (13) | 70 | F T2DM, HTN, OA, AF, meningioma | 8-mm right adrenal nodule, 3 HU | Nonfunctioning | 7 years | Yearly CT for 5 years. CT at year 3 showing increase in density to 30 HU but stable size. | CT AP at year 7: 66 mm right adrenal lesion, HU 32 | None | 90-mm ACC; Ki67 20%; Weiss score 5 | None | Open right adrenalectomy and partial hepatectomy. Local recurrence and metastasis, death 1 year after diagnosis. |
| Belmihoub et al 2017 (14) | 71 | M Myelodysplasia, recurrent UTI | 17-mm right adrenal nodule, HU 7.9 | Nonfunctioning | 13 years | CT at years 1, 3, and 5. | CT AP at year 15: 60-mm heterogeneous mass, HU 25 | None | ACC; Ki67 30%; Weiss score 8 | None | Right adrenalectomy. CT scan 5 months |
| postoperatively showed local | |||||||||||
| recurrence with liver, lung and peritoneal metastases. Died 2 months later. | |||||||||||
Abbreviations: AF, atrial fibrillation; CT AP, computed tomography scan of abdomen and pelvis; EDP, etoposide; doxorubicin, and cisplatin; FDG-PET, fluorodeoxyglucose positron emission tomography; HTN, hypertension; HU, Hounsfield units (on unenhanced CT, unless otherwise specified); OA, osteoarthritis; T2DM, type 2 diabetes; UTI, urinary tract infection.
| Demographics | Identification and monitoring of adrenal adenoma | Apparent transformation to ACC | Treatment and outcome | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Case | Age at initial nodule detection | Sex Other medical comorbidities | Initial imaging | Initial biochemical assessment | Time to ACC diagnosis | Interval imaging | Imaging at diagnosis of ACC | Hormone secretion | Histopathology | Metastases at diagnosis | |
| Gagnon | 32 | F Urolithiasis, IBS, | 29-mm left adrenal | Nonfunctioning | 10 years | MRI at year 2-24 mm, | CT at year 10: 90-mm | Cortisol, | 120 mm ACC; Ki67 | Lung, liver | Treated with mitotane and |
| et al | fibromyalgia | nodule, 31 HU | no loss of signal on | left adrenal lesion | androgens | 30%; Modified | EDP. VUS found in APC | ||||
| 2020 | out of phase | Weiss score 6 | gene. | ||||||||
| (29) | imaging. | ||||||||||
| CT at year 2: 25 mm, | |||||||||||
| 20 HU. | |||||||||||
| CT at year 4: 25 mm, | |||||||||||
| 23 HU. | |||||||||||
| Kohli et | al 61 | F HTN, Crohn disease, | 20-mm left adrenal | Nonfunctioning | 9 years | CT scan at year 1, 4, 5, | CT AP at year 9: | Cortisol | 80 mm ACC; Ki67 | None | Left adrenalectomy. Adjuvant |
| 2021 | Osteopenia | nodule, HU >10, | and 7 stable | 58 mm left adrenal | 20%-30%; Weiss | radiotherapy and mitotane. | |||||
| (30) | absolute washout, | lesion, 37 HU | score not | Developed lung and | |||||||
| 67% and relative | reported | peritoneal metastases. Died | |||||||||
| washout >47% | 15 months after diagnosis. | ||||||||||
| Aono et | al 68 | F HTN, RA | 16-mm left adrenal | Incomplete | 9 years | CT scan at year 3 and | CT at year 9: 54-mm | Cortisol | 70-mm ACC; Ki67 | None | Adjuvant mitotane. Local |
| 2022 | nodule, 30 HU | year 5 stable. | heterogeneous left | 20%; Weiss 4. | recurrence at 18 months | ||||||
| (31) | CT scan at year | adrenal lesion, HU | postoperatively treated | ||||||||
| 8-30 mm, | not reported | with radiotherapy. | |||||||||
| irregular. | |||||||||||
| Ros et al | 74 | F HTN, IHD, PAD, AF, | 14-mm left adrenal | Primary | 7 years | CT scan year 5 both | CT year 7: 35-mm left | None | 38-mm ACC; Ki67 | None reported | Adjuvant mitotane |
| 2024 | COPD, CKD3, | nodule, 23 HU | aldosteronism | nodules stable | adrenal lesion, | 50%-60%; Weiss | |||||
| (32) | osteoporosis, | with absolute | size. FDG-PET mild | 40 HU | 6 | ||||||
| hypothyroidism | washout 84% and | uptake in both | |||||||||
| relative washout 71%. | adrenal nodules. | ||||||||||
| CT year 6: 25-mm left | |||||||||||
| 6 mm left adrenal nodule 20 HU with | adrenal nodule | ||||||||||
| absolute washout 67% and relative | |||||||||||
| washout 43%. | |||||||||||
Abbreviations: CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CT AP, computed tomography of the abdomen and pelvis; EDP, etoposide, doxorubicin, and cisplatin; HTN, hypertension; HU, Hounsfield units (on unenhanced CT, unless otherwise specified); IBS, irritable bowel syndrome; IHD, ischemic heart disease; PAD, peripheral arterial disease; RA, rheumatoid arthritis; VUS, variant of unknown significance.
A
A
B
37 mm
52 mm
16
Min: - 133 Max: 87 (HU)
Average: - 10.09 StdDe
C
D
[18F]FDG uptake on 2 occasions, the adrenal MDT felt the lesion was still most likely to represent a lipid-poor adenoma. A urine steroid profile was requested that identified relative increases in the 17-hydroxyprogesterone metabolite pregnanetriol and the progesterone metabolite pregnanediol, alongside a relative increase in one of the ACC markers 5-pregnene-3a,16a,20-triol. However, this report was not considered conclusive for the pres- ence of ACC and, taking into account the size of the adrenal le- sion (<4 cm) and stability over time, after discussion with the patient, a decision was taken to continue with regular surveil- lance imaging. Interval CT 12 months later revealed a significant increase in size of the adrenal lesion to 57 x 72 mm (Fig. 3). Given the patient’s history of an extra-adrenal malignancy, and the im- portance of distinguishing between an adrenocortical and a non- adrenocortical lesion, para-chloro-2[18F]fluoroethyletomidate ([18F]CETO) PET-CT (which, similar to [11C]MTO PET, specifically localizes tissues expressing CYP11B1 and CYP11B2) was per- formed and showed heterogeneous, avid [18F]CETO uptake in the right adrenal lesion confirming its adrenocortical origin. Repeat [18F]FDG PET-CT now demonstrated heterogeneous high uptake in the right adrenal lesion. There were no other
[18F]CETO or [18F]FDG-avid lesions suggestive of metastatic dis- ease. She was referred for right adrenalectomy and histology confirmed a 100-mm adrenocortical carcinoma (Table 1).
Cases from the literature
Four case reports were identified describing patients with ACC who had evidence of a preexisting ipsilateral adrenal lesion that was deemed at baseline to be consistent with an adenoma (lesion size <4 cm with unenhanced CT attenuation ≤20 HU) (Table 2). Of note, 3 of the 4 cases documented unenhanced CT attenuation values of <10 HU on initial imaging and all cases reported stability in lesion size on serial CT surveillance over a 5- to 13-year interval. None of the cases had evidence of hormonal hypersecretion at baseline assessment, but 1 subsequently de- veloped cortisol excess and a further case developed mixed cor- tisol and androgen excess. Importantly, the cases reported by Angelousi et al (11). and Parry et al (13). both showed an increase in unenhanced attenuation during CT surveillance (<10 to 24 HU and 3 to 30 HU, respectively) prior to demonstrating an increase
In phase
Out of phase
in lesion size. This mirrors the observed change in unenhanced CT attenuation from 19.6 to 33 HU prior to significant dimension- al change in Case 2 reported here.
Four further cases reporting indeterminate (lesion size <4 cm and unenhanced attenuation >20 HU) or incompletely charac- terized adrenal lesions, which exhibited a prolonged period of absent or indolent growth prior to diagnosis of ACC are summar- ized in Table 3. All 4 cases had prolonged size stability on serial imaging and 2 of the 4 cases also underwent immediate further characterization with reassuring absolute (>60%) and relative (>40%) washout on delayed contrast-enhanced CT.
Two studies have focused on the identification of preexisting adrenal lesions in patients subsequently found to have an ACC. In a retrospective single-center study by Nogueira et al., 20 of 422 patients (4.7%) with ACC had radiological evidence of ad- renal nodules 5 months or more prior to diagnosis. Six of 20 pa- tients were reported as having a latent period of relative stability (defined by the authors as minimal growth), with 1 patient dem- onstrating dimensional lesion stability for 8 years prior to an ac- celerated growth phase. However, information regarding the serial interval imaging performed was not reported for individual patients and the reported rate of growth calculated by the au- thors was presented as an average (representing the increase in size between initial imaging and imaging at diagnosis of ACC/time in years), which does not reflect the variable growth rate trajectories of individual patients (18). In a second retro- spective study looking at delayed diagnosis of ACC, Ozsari et al. identified 25 of 439 patients with preexisting cross- sectional images for review and found 20 of 25 patients had pre- existing adrenal masses on imaging >3 months prior to ACC diag- nosis. Again, this study demonstrated the variable growth trajectories of these preexisting lesions. One patient who had an initial lesion size of 25 mm and unenhanced density of 17 HU showed radiological stability at 24 and 48 months, fol- lowed by accelerated growth and eventual diagnosis of a 53 mm ACC at 72 months. Other reported patients had a signifi- cantly more rapid growth trajectory (19). However, in both case series, no patients had a baseline unenhanced density of <10 HU
(18, 19). Because of the incomplete phenotypical data, these cases reported in Nogueira et al. and Ozsari et al. have not been included in Table 3.
Three examples of ACC detected within a hyperplastic or aden- omatous lesion on histopathological examination have also been reported, with 2 cases undergoing comparative genetic analysis of the different components (15-17). Bernard et al. re- ported an incidentally detected 55-mm adrenal lesion associated with MACS, which upon pathological examination was found to contain a 22-mm central malignant component (Weiss score 5, Ki67 > 10%) surrounded by a rim of tissue with a benign appear- ance (Weiss score 0, Ki67 < 1%). The central malignant compo- nent was associated with p53 loss of heterozygosity and overexpression of IGF2 in contrast to the benign-appearing periph- eral tissue (16). Dybal et al. reported a 45-mm right adrenal lesion associated with MACS, which on histopathological examination was found to comprise a central 27-mm core of ACC (Weiss score 5, Ki67 40%) embedded within a benign clear-cell rich nodule. Although the benign-appearing region of the nodule had heterozy- gous deletion of CDKN2A and an ARID1A exon 20 variant, the adja- cent ACC cells had somatic homozygous deletions of CDKN2A, CDKN2B and MTAP, TERT amplification, CTNNB1 mutation, ARID1A exon 20 variation, and ARID1A loss of heterozygosity. The patient had previously undergone a contralateral adrenalectomy for an adenoma associated with cortisol excess, but none of the bilateral macronodular adrenal hyperplasia (BMAD) associated germline mutations had been identified (15)
Discussion
We report 2 patients from 2 tertiary centers within the United Kingdom (Table 1) and a further 4 cases from the literature (Table 2) who demonstrated benign radiological characteristics at baseline, but were subsequently diagnosed with ACC. All 6 pa- tients had serial adrenal imaging demonstrating dimensional stability for up to 14 years. Three of the 6 patients demonstrated an increase in unenhanced density prior to an increase in growth
A
80 mm
28 mm
29 mm
37 mm
72 mm
Nodule detection
+4years
+11years
+12years
+12.5years
+8years
+12.5years
rate and 1 patient had an abnormal urine steroid profile. A fur- ther 3 examples of ACC embedded within a hyperplastic or aden- omatous lesion were also identified in the literature.
We also identified 4 case reports of indeterminate adrenal nodules that showed prolonged lesion stability or indolent growth (the fastest being ~3 mm/year) for up to 10 years prior to an accelerated growth phase and diagnosis with ACC (Table 3). Several additional examples of ACCs with a prolonged period (up to 8 years) of dimensional stability were identified within 2 case series but were missing individualized case infor- mation regarding radiological surveillance.
The mean time to ACC diagnosis for patients with benign radiological characteristics at baseline (lesion size <4 cm and unenhanced density ≤20 HU; Tables 1 and 2) was 10.5 years (range, 5-14 years), and for patients with indeterminate radio- logical characteristics at baseline (lesion size <4 cm and unen- hanced density >20 HU or incompletely characterized; Table 3) that was 8.75 years (range, 7-10 years). The difference between these 2 groups in the average time to ACC diagnosis was not stat- istically significant on Student t-test analysis (P =. 39). The growth trajectory of an adrenal lesion prior to diagnosis with ACC is evidently variable, with some lesions demonstrating di- mensional stability over several years.
The adenoma to carcinoma sequence is well established for colorectal cancer. Mutation in the APC tumor suppressor gene, which is a component of the @-catenin (CTNNB1) destruction complex, is widely accepted as a common initiating event for colorectal adenoma development. Different pathways have been established for the colorectal adenoma-carcinoma
transition following this, including that of chromosomal instabil- ity, driven primarily by Wnt signaling pathway activation, KRAS activation and TP53 mutations, or the microsatellite instability pathway where loss of mismatch repair gene function causes progressive accumulation of somatic base pair mutations (20). This sequential transition has not been proven in the adrenal gland, though the 6 cases that we describe and 3 additional re- ports of adrenocortical carcinoma embedded within an aden- oma indicate that it may be possible. Most case series of adrenal incidentalomas, however, do not report progression to malignancy (2), and it is likely that it remains a rare event.
Transcriptome analysis of adrenocortical tumors shows dis- crete clustering of adrenocortical tumors into 3 subtypes, name- ly C1a, C1b, and C2, which correspond to an aggressive group of ACC with high expression of cell-cycle genes, a less aggressive ACC group with an immune signature, and a high adrenal differ- entiation group representing adenomas, respectively (21-24). Mutations in ß-catenin (CTNNB1) are present in up to 30% of both adrenocortical adenomas and carcinomas, suggesting that the constitutive activation of the Wnt/ß-catenin signalling pathway may be an early step in tumorigenesis (25, 26). Notch mutations are also commonly reported in both adrenocortical adenoma and carcinoma (27). As seen in the reported cases of ACC embedded within a benign lesion, IGF2 overexpression, however, is specific to ACC, and ACCs have a higher number of genomic alterations (15, 16, 27). Mouse models suggest that both altered B-catenin and IGF-2 expression may be required to transition from adrenal hyperplasia to tumorigenesis (28). In ACC, key driver genes are CTNNB1, TP53, CDKN2A, RB1, and
MEN1, with a study also identifying ZNRF3 as a tumor suppressor gene altered in 21% of cases (22). Interestingly, Jouinot et al. studied a subgroup of histopathologically heterogeneous ACCs and demonstrated that the transcriptome analysis of the benign-appearing components was concordant with that of the more histopathologically aggressive parts (23). Further research is required to understand if, and how, the stepwise progression from adrenal adenoma to carcinoma occurs, or if these cases re- present independent or collision tumour events.
The potential rare occurrence of transformation from adrenal adenoma to ACC poses a challenge for clinicians, who need to balance increased surveillance for early detection of ACC with the risks of iatrogenic harm from radiation exposure or incidental findings, and the financial burden of repeated abdominal im- aging in resource-limited settings. It is important to emphasize that the 2 cases reported from our tertiary centers represent ap- proximately 0.1% of all referrals to 2 large tertiary center adrenal MDTs over a 4-year period.
However, our cases demonstrate that lesion size stability can be falsely reassuring. One observation from this case series and literature review was that for 3 of our 6 reported patients with baseline unenhanced density of <10 HU, an increase in unen- hanced density was seen prior to an increase in size. While this change in unenhanced density may lead the MDT to consider fur- ther interval imaging rather than discharge, an important caveat is that unenhanced density can only be applied to radiologically homogenous adrenal lesions and can be a subjective measure- ment, relying on an experienced radiologist. Case 2 also demon- strates the utility of urine steroid profile assessment in the evaluation of indeterminate adrenal nodules, though further prospective studies to evaluate the utility of urine steroid profile for indeterminate nodules of <4 cm size are needed.
Many patients with adrenal lesions that are characterized as radiologically indeterminate (unenhanced HU >20, heteroge- neous appearance) will be recommended for an adrenalectomy. However, patients that are managed with radiological surveil- lance due to comorbidities or personal preference should be counseled that ACC remains a possibility even if the lesion is sta- ble for >12 months. In this case series and literature review, we have reported 4 cases that were stable on serial imaging for >12 months (Table 3) and for whom the mean time to accelerated growth was 8.75 years. This suggests that if surveillance of radio- logically indeterminate lesions is chosen as the preferred option patients should be counseled that exclusion of an ACC may re- quire many years of radiological surveillance.
A limitation of this retrospective literature review is that we are likely to have selected the most indolent cases of ACC due to our predefined criteria of lesional stability for >12 months. It is not possible to accurately quantify the proportion of patients with radiologically indeterminate lesions who go on to develop ACC after a prolonged period of stability of >12 months, as most pa- tients would either be offered adrenalectomy after baseline as- sessment or would be discharged after 12 months of follow up. A further limitation of this case series is that a histopathological diagnosis was not available for case 1; however, the authors be- lieve that the presence of adrenocortical tissue in the lungs as demonstrated by [11C]MTO uptake on PET-CT is most in keeping with a diagnosis of metastatic ACC.
In conclusion, adrenal lesions with baseline benign radiological characteristics can very rarely transpire to be ACC. Prolonged
lesional stability cannot be considered a reassuring feature in iso- lation when assessing radiologically indeterminate adrenal le- sions in the adrenal MDT and this case series and literature review demonstrates that a small risk of ACC remains even after >10 years of dimensional stability. Further research to under- stand the molecular mechanisms underpinning a possible ad- renal adenoma to carcinoma transformation would be valuable and this article highlights the need for additional prognostic bio- markers for stratifying risk in radiologically indeterminate lesions.
Funding
This research article received no external funding.
Disclosure
The authors have no conflicts of interest to disclose.
Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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