ENDOCRINE SOCIETY
OXFORD
Transformation of a Benign Adrenocortical Adenoma to a Metastatic Adrenocortical Carcinoma Is Rare But It Happens
Anna Angelousi,10 Anne Jouinot,2 Charis Bourgioti,3 Panagiotis Tokmakidis,4 Jérôme Bertherat,2 and Gregory Kaltsas4
1First Department of Internal Medicine, Unit of Endocrinology, Laikon Hospital, Center of Excellence of Endocrine Tumours, National and Kapodistrian University of Athens, 11527 Athens, Greece
2Université de Paris, Institut Cochin, Department of Endocrinology, Referral Center for Rare Adrenal Diseases, INSERM U-1016, CNRS UMR- 8104, 75014 Paris, France
3Department of Radiology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion Hospital, 11528 Athens, Greece 4Neuroendocrine Tumor Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
Correspondence: Anna Angelousi, PhD, First Department of Internal Medicine, Unit of Endocrinology, Laikon Hospital, National and Kapodistrian University of Athens, 17th Mikras Asias St, 11527 Athens, Greece. Email: a.angelousi@gmail.com.
Abstract
The transformation of an adrenocortical adenoma (ACA) to an adrenocortical carcinoma (ACC) is extremely rare. Current guidelines suggest against further imaging studies and follow-up in patients with nonfunctional adrenal incidentalomas (NFAIs) with benign imaging characteristics. Herein, we present a 64-year-old male patient diagnosed initially with a NFAI of 3 cm in size with imaging characteristics consistent with an ACA. However, 13 years after initial diagnosis, this apparent ACA developed into a high-grade cortisol and androgen-secreting ACC with synchronous metastases. The literature review revealed a further 9 case reports of adrenal incidentalomas initially characterized as ACA that subsequently developed into ACC within a period ranging from 1 to 10 years. The pathogenesis of transformation of an initially denoted ACA to ACC is not fully delineated, although the existing literature focuses on the preexisting or changing genetic background of these lesions, highlighting the need to develop robust prognostic markers to identify patients at risk and individualize the follow-up of these unique cases.
Key Words: adrenal incidentalomas, adrenocortical carcinoma, adrenal adenoma, adrenal incidentaloma, malignant transformation, malignant evolution
Introduction
The incidence of adrenal tumors discovered often on cross- sectional abdominal imaging ranges between 5% and 7% of patients, increasing with age (1). Over the last 2 decades, the incidence of adrenal tumors has increased 10-fold, in parallel to the increase of abdominal computerized tomography (CT) and magnetic resonance imaging (MRI) studies performed (2). Malignant transformation of an adrenal incidentaloma (AI) considered to be an adrenocortical adenoma (ACA) to an adrenocortical carcinoma (ACC) is extremely rare, with an in- cidence of less than 1% (2). However, this figure varies ac- cording to the size of ACAs, ranging from 2% for tumors of 4 to 6 cm to 25% for tumors >6 cm (3).
Recent guidelines recommend that all AIs should be eval- uated initially with a noncontrast CT to estimate their lipid content as well as their appearance whether it is homogenous or not (4). If the noncontrast CT is consistent with a benign adrenal mass with a baseline density of <10 Hounsfield (HU), no further imaging is suggested. Although such an ap- proach is cost-effective and reduces the burden of regular in- vestigations along with the danger of radiation exposure, rare cases of ACCs that were initially diagnosed as ACAs have been described (5-13).
Herein, we report the case of a 64-year-old male patient di- agnosed with a nonfunctional ACA that transformed (the pro- cess that a normal cell undergoes as it becomes malignant) into a metastatic ACC 13 years after initial diagnosis. An extensive review of the literature has also been performed including cases with an initial diagnosis of AI with benign characteristics that subsequently transformed to ACC.
Case Presentation
A 64-year-old male smoker with a history of hypertension was diagnosed incidentally with a 3 cm homogenous lesion of the left adrenal following an abdominal CT performed for ab- dominal discomfort in 2010. The lesion had a density of <10 HU and thus was in favor of an ACA. Hormonal workup showed no evidence of hormonal hypersecretion (Table 1). Since then, the patient has undergone abdominal imaging yearly for the first 3 years and then every 2 years. The size and the imaging characteristics of the lesion remained stable until 2017 when he was lost to follow-up for the next 4 years. A CT scan performed in 2021 showed a stable lesion of 3 cm albeit with higher unenhanced attenuation values of 24 HU (Fig. 1). Hormonal screening revealed no hormonal hyperse- cretion. However, 2 years later he presented with significant
| Biochemical parameters | Reference range and units | Initial diagnosis | Follow-up 2 years before ACC diagnosisª | 13 years of follow-up | 6 months posttreatment |
|---|---|---|---|---|---|
| Cortisol (am) | 6-17 µg/dL (165-468 nmol/L) | 14.8 µg/dL (408 nmol/L) | ND | 15.30 µg/dL (422 nmol/L) | 12 µg/dL (331 nmol/L) |
| ACTH | 15-57 pg/mL (3.3-12.5 pmol/L) | 18.3 pg/mL (4 pmol/L) | ND | 27 pg/mL (5.9 pmol/L) | 248 pg/mL (54.6 pmol/L) |
| DHEAS | 33-249 µg/dL (0.89-6.7 µmol/L) | 58 µg/dL (1.5 µmol/L) | 42 µg/dL (1.1 µmol/L) | 410 µg/dL (11 µmol/L) | 8.9 µg/dL (0.2 umol/L) |
| 17-OH progesterone | 0.5-2.1 ng/ml (1.5-6.35 nmol/L) | 1.4 ng/ml (4.2 nmol/L) | ND | 33.8 ng/ml (102 nmol/L) | 1.07 ng/ml (3.2 nmol/L) |
| Aldosterone | 2-9 ng/dL (55-250 pmol/L) | 9.16 ng/dL (254 pmol/L) | ND | 9.7 ng/dL (269 pmol/L) | 4.37 ng/dL (119 pmol/L) |
| PRA | 0.2-2.35 ng/ml/ hour | 1.34 ng/ml/hour | ND | 1.2 ng/ml/hour | 0.2 ng/ml/hour |
| Testosterone | 1.9-7.7 ng/ml (5.8-26.7 nmol/L) | 5.9 ng/ml (20.4 nmol/L) | ND | 2.2 ng/ml (7.6 nmol/L) | 0.7 ng/ml (2.63 nmol/L) |
| SHBG | 190-722 µg/dL (20-76 nmol/L) | ND | ND | 313.5 µg/dL (33 nmol/L) | 1900 µg/dL/L (>200 nmol) |
| 44 androstenedione | 0.6-3.3 ng/ml (2.09-11.5 nmol/L) | ND | ND | 4.3 ng/ml (15 nmol/L) | 0.82 ng/ml (2.8 nmol/L) |
| UFC | 20-133 µg/24h (55-365 nmol/24 hours) | 100.5 µg/24 hours (276 nmol/24 hours) | 67.6 µg/24h (182.5 nmol/24 hours) | 203 µg/24h (560 nmol/24 hours) | 179 µg/24 hours (494 nmol/24 hours) |
| Cortisol (1 mg ODST) | <1.8 µg/dL (49 nmol/L) | 1.7 µg/dL (46.8 nmol/L) | 1.8 µg/dL (49 nmol/L) | 9 µg/dL (248 nmol/L) | ND |
Abbreviations: AI, adrenal incidentaloma; ACC, adrenocortical adenoma; DHEAS, sulfate dehydroepiandrosterone; ND, no data; ODST, overnight dexamethasone suppression test .; PRA, plasma renin activity; UFC, urinary free cortisol.
“At the time of imaging changes (increased Hounsfield units).
A
2010
B
2013
C
2017
D
2021
2
Mean=7.072 SD=16.37 Max=46 Min =- 35 Area=0.686 cm2 (84 px)
Mean=3.426 SD=27.85 Max=68 Min =- 76 Area=0.6618 cm2 (134 px)
Mean=24.95 SD=19.83 Max=72 Min =- 30 Area=0.4782 cm2 (89 px)
0
d
D
2023
A
B
C
B
D
weight loss during a 3-month period, associated with fatigue and abdominal pain. An abdominal CT showed a heteroge- neous left adrenal lesion measuring 12 × 11.5 × 8.6 cm exhib- iting diffuse infiltration to the surrounding structures (Fig. 2). MRI confirmed the presence of an enlarged heterogeneous left adrenal mass with intense contrast enhancement (Fig. 3A-3C). In addition, 2 new suspicious lesions were described in the liv- er, 1 of 2 cm in segment VIII and another of 7.7 mm in segment VI, in favor of metastatic disease (Fig. 3A-3C). A thoracic CT also showed multiple secondary bilateral pulmonary lesions (Fig. 4A). 18F-fluorodeoxyglucose positron emission tomog- raphy (18FDG-PET) showed increased uptake of the adrenal lesion (18 SUVmax), of the hepatic and pulmonary lesions (10-12 SUVmax) and of the left adrenal vein (12 SUVmax) consistent with a vascular thrombus (Fig. 2).
Diagnostic Assessment
Clinically the patient was cachectic and normotensive without any signs of Cushing syndrome. The hormonal profile
demonstrated excessive cortisol and androgen secretion (Table 1). A biopsy of 1 of the liver lesions confirmed metas- tasis from a high-grade ACC with a Ki-67 labeling index (LI) of 70%. Immunohistochemical analyses were positive for steroidogenic factor 1, synaptophysin+, and melan A+ and negative for pankeratin, epithelial membrane antigen, and chromogranin A. Molecular classification based on transcrip- tome analysis of the hepatic metastasis was performed using 3’ RNA-sequencing from formalin-fixed paraffin-embedded sample, as previously described (14). The sample was clas- sified as “C1A,” which is considered predictive of a poor outcome (Fig. 5).
Treatment
The case was presented to the multidisciplinary board where it was decided that no surgical operation was feas- ible and the patient was started on high-dose mitotane (maximum 6 g) treatment, achieving levels of 22.5 mg/L within 8 weeks albeit with significant side effects
A
B
C
D
E
F
A
B
necessitating titration of the mitotane dose to 4.5 g daily. Replacement treatment with hydrocortisone along with fludrocortisone was also needed. The patient received con- comitantly 6 cycles of chemotherapy (etoposide, doxorubi- cin, and cisplatin) based on the FIRMACT study (15).
Outcome and Follow-up
Grade 3 side effects including nausea, fatigue, instability, neu- rosensorial symptoms, and difficulties in memory and concen- tration developed 2 to 3 weeks after the initiation of both mitotane and chemotherapy treatments. In addition, the
40-
20-
*
Col.
PC2
C1A
0
C1B
C2
-20-
-40-
-20
1
-40
0
20
40
PC1
patient developed an osteoporotic right colles fracture neces- sitating the administration of denosumab.
Imaging 3 months postinitiation of both treatments showed a partial response of all lesions and at 6 months a further par- tial response based on RECIST 1.1 criteria of the adrenal and the hepatic lesions (Fig. 3D-3F) with complete resolution of the lung metastases (Fig. 4B). The patient is still alive 8 months after ACC diagnosis and continues only on mitotane treat- ment due to his poor performance status.
Discussion
We describe a rare case of a patient diagnosed initially with a 3 cm nonfunctional ACA that transformed after 13 years of follow-up to a metastatic ACC. Although it is not possible to define the exact timing of transformation, it most likely oc- curred 11 years after the initial diagnosis of ACA and 2 years before the diagnosis of the ACC when a change in the en- hanced attenuation value occurred besides the lesion being stable in size.
Recent European Society of Endocrinology clinical practice guidelines for the management of AIs suggest against any
further imaging of adrenal masses <4 cm in size with clearly benign radiological features that are functionally inactive (4). However, in patients with indeterminate radiological find- ings, further imaging after 6 to 12 months is suggested, with either CT/MRI or even 18FDG-PET. Thus, in the present case, the initial diagnosis of a benign nonfunctioning ACA should have been made and no further follow-up would have been suggested.
A literature search through PubMed identified 9 additional ACC cases reported from 2017 to 2024 that were initially di- agnosed as ACA of <4 cm with mostly benign imaging char- acteristics that transformed to ACCs (Table 2) (5-13). Hormonal investigations demonstrated that 3 were functional (6, 8, 11). All cases were initially evaluated with a CT scan, and in 3 cases an MRI was additionally performed (6, 11, 13). Six cases had typical characteristics of ACAs on CT scan exhibiting low unenhanced attenuation values of <10 HU (5, 7, 8, 9, 10, 11) whereas in the remaining 3 (6, 12, 13), the findings were ambiguous (Table 2).
A further retrospective study of 439 ACCs demonstrated that 20 were characterized as AIs with a median initial size of 2.8 cm (16). However, all presented atypical CT
| Ref | Age, Sex(F/ M) | Initial symptom, lateralisation | Initial size | Initial CT/MRI features | Initial hormonal profile | Last CT/MRI before ACC diagnosis: time/size | ACC characteristics on imaging (CT/MRI) | Time to progression from initial diagnosis | Final size, increase per year | Hormonal hypersecretion on FU | Histology |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Parry et al 2024 (5) | 70 y F | Flushing, right AI | 8 mm | 3 HU (noncontrast)/ND | NF | 2y/8 mm ACA (stable for 6 y) | 32 HU noncontrast (washout = 0%) | 7 y | 66 × 49 mm, 29 mm/y | NF | ACC, Weiss:5, Ki-67:20%, (stage II) |
| Ohkubo et al 2024 (6) | 50 y, F | Fever, right AI | 20 × 20 mm | 32 HU (noncontrast), delayed washout/lipid-rich | Hyperaldosteronism | ND | Enlarged size | 1 y | 130 mm, 110 mm/y | Cortisol and aldosterone | ACC, Weiss:7, Ki-67:36% |
| Kohli et al 2021 (7) | 70 y, F | No relevant symptoms, left AI | 20 x 16 mm | >10 HU (noncontrast) with 67% absolute washout and 47% relative wash out/ND | NF | 1y/20 × 16 mm ACA (stable for 7 y) | 37 HU noncontrast, 98 HU postcontrast | 8 y | 58 × 43 mm, 38 mm/y | Cortisol | ACC, Ki-67:30%, (stage II) |
| Aono et al 2022 (12) | 77 y, F | No relevant symptoms, left AI | 15 × 16 x 15 mm | 30 HU, homogeneous, rounded/ND | NF | 1y/21 x 28× 30 mm ACA (stable for 6 y) | Heterogenous with cystic degeneration/No signal loss in the out of phase | 9 y | 35 × 41 × 54 m, 14 mm/y | Cortisol | ACC, Weiss:4, Ki-67:20%, CTNNB1, G34A mutation |
| Gagnon et al 2020 (13) | 32 y, F | Non specific abdominal pain, left AI | 29 × 19 mm | 31 HU/isointense in T2 with few hyperintense areas, no loss of signal in the out of phase | NF | 6y/29 x 19 mm ACA (stable for 5 y) | Two new hepatic lesions | 10 y | 90 × 82 mm, 10 mm/y | Cortisol and androgens | ACC, Ki-67:30%, APC mutation |
| Rebielak et al 2019 (8) | 28 y, F | Left flank pain, left AI | 27 × 21 mm | In favor of ACA/ND | Elevated total/free testosterone | 7y/27 × 21 mm ACA (stable for 7 y) | 25% absolute washout/47 x 59 mm enhanced left adrenal mass | 7 y | 56 × 37 × 40 mm, 4 mm/y | Testosterone | ACC, Ki-67:30%, (stage II) |
| Barsukova et al 2019 | 72 y, F | ND, left AI | -2007: 15 mm | -2007: In favor of ACA/ND -2016: 15 HU with 42% relative washout/ND -2018: ND/large lobulated heterogeneous mass | 2007:NF 2016: hypercortisolaemia 2018: recurrence of hypercortisolaemia (adrenalectomy) | 2 y (post-adrenalectomy) | Heterogeneous with new nodules superior and | -NF to cortisol-secreting | 68 × 41×59 mm, 34 mm/y | Cortisol | -1st surgery Weiss:2 (ACA) -2nd surgery: ACC |
| (11) | -2016: 37 mm -2018: 68mm | posterior to kidney | ACA: 9 y - Recurrence postsurgery: 2 y | ||||||||
| Thuzar et al 2018 (9) | 47 y, F | No relevant symptoms, left AI | 13mm | In favor of ACA/ND | NF | 10 m/20 x 15 × 17mm | Large heterogenous atypical mass | 3 y | 100× 90× 130 mm, 80 mm/y | NF | ACC, Weiss:5, Ki-67:40%, (stage II) |
| Belmihoub et al 2017 (10) | 71 y, M | Urinary tract infection, right AI | 17 mm | In favor of ACA/ND | NF | 5y/21 mm (9 HU) | 5 HU noncontrast, < 50% absolute washout/No signal loss in the out-of-phase | 8 y | 60 mm, 8 mm/y | Cortisol | ACC, Weiss:8, Ki-67:30% (stage II) |
Abbreviations: ACA, adrenocortical adenoma; ACC, adrenocortical carcinoma; AI, adrenal incidentaloma; CT, computerized tomography; F, female; FU, follow-up; HU, Hounsfield units; M, male; MRI, magnetic resonance imaging; ND, no data; NF, nonfunctioning; y, years.
characteristics, with ether median precontrast density of 36 HU or heterogeneous adrenal mass or calcification (17). Another retrospective study, including 422 ACCs, showed that 20 had previously been diagnosed as ACAs measuring <4 cm in size. However, only 2/20 ACCs exhibited imaging characteristics suggestive of a benign lesion (17).
Recently, it was shown that a growth rate of 3 mm/year could distinguish ACA from malignant lesions with 100% sensitivity and specificity (18). However, 7 cases in the litera- ture presenting initially with ACAs that remained stable in size for the first 5 to 7 years were diagnosed as ACCs after 7 to 10 years from the initial diagnosis of ACAs (5, 7, 8, 10, 11, 12, 13). Thus, surveillance with imaging during only the first 5 years from initial diagnosis would have missed the malignant transformation of these ACAs to ACCs. Moreover, a retro- spective analysis showed that the combination of an adrenal tumor size of 3 cm with an unenhanced attenuation value of 20 HU or of 4 cm with an unenhanced attenuation value of 15 HU was associated with a 100% positive predictive value for the diagnosis of ACA (19).
The transformation of an initially denoted ACA to ACC has been described not only with respect to imaging characteris- tics but also their hormonal profile. Five tumors initially characterized as nonfunctioning ACAs transformed to cortisol-secreting ACCs similar to our case (6, 7, 10, 12, 13).
In 8 of the 9 described cases, surgery was the first line treat- ment and histology demonstrated in 7 of them high-grade ACCs. Our ACC was also classified as high-grade ACC with a Ki-67 LI value of 70%.
The transformation of ACA to ACC is largely questioned due to the increased frequency of the former and the rarity of the latter entity. Whether ACCs develop from benign aden- omas or represent a de novo event has not been fully clarified. Some authors support the hypothesis of the independent de- velopment of 2 distinct tumors, derived from separate clones in the same adrenal gland that are histologically distinguish- able, with 1 central malignant tissue and an adjacent benign adrenal tissue (20, 21). However, the absence of benign tissue could be explained by the aggressivity and the invasion of the malignant tumor as described in 1 case report (10). The se- cond hypothesis suggests that adrenal tumorigenesis is a pro- gressive multistep procedure transforming normal adrenal tissue to ACA and eventually to ACC (22).
Recently, several prognostic scores have been developed based on histopathological markers, such as Ki-67 LI, number of mitoses (Helsinki score), or combining histological and clinical variants (S-GRAS score) (23). The genetic analysis seems to present the cornerstone of the progress made regard- ing the prediction of ACC behavior. Several molecular param- eters such as Wnt/B-catenin pathway alterations increased p53 expression, insulin growth factor-II overexpression, hyperme- thylation of CpG loci, and overexpression of several miRNAs allow classifying these tumors based on their genetic profile ei- ther in the C1A (poor outcome ACC) or C1B (better outcome ACC) group (14, 24) (Fig. 5).
A large series including 512 ACC cases reported that 38% were diagnosed incidentally with a frequency increasing with age (25). In contrast to a previous retrospective study (17), ACCs found incidentally were less aggressive, presenting also better prognosis compared with the symptomatic ones (25). The clinical history of the 10 cases initially diagnosed as benign ACAs showed that only half were completely asymptomatic and could be characterized as “true AI.” In 3
patients (7, 9, 12) as in our case, a pre-existing atypical ab- dominal symptom led to the performance of further imaging, whereas in 1 case, this information was not available (11).
A meta-analysis performed almost 15 years ago showed that the risk of an AI developing into a functional ACA or an ACC during follow-up is rare accounting for <1% and 0.2% of cases, respectively (26). Most importantly, during the follow-up, the risk of false-positive cases was 50 times greater than the true-positive ones. Additionally, the average radiation exposure during a CT scan was associated with a 1/430 to 2170 chance of developing cancer similar to the like- lihood of developing adrenal malignancy during a 3-year follow-up of AIs (26).
In conclusion, ACC is a rare disease, and ACC originating from an ACA is an even rarer event, but it does exist. Imaging follow-up of AIs with benign imaging characteris- tics has been modified according to recent guidelines to avoid excessive investigations. Considering the potential implications of continuous monitoring and unnecessary ra- diation exposure to identify patients who could be at risk for developing ACCs, additional predictive biomarkers need to be developed to potentially identify patients who may exhibit such a course.
Learning Points
· ACC incidence among AI is generally rare, and transform- ation of an ACA to an ACC is extremely rare but exists.
· No robust radiological features are currently available that can help to predict ACA at risk of transforming to ACC.
· The identification of such predictive biomarkers presents an unmet need and should probably be based on the gen- etic profile of these tumors.
Contributors
All authors made individual contributions to authorship. G.K. and A.A. were involved in the diagnosis and management of the patient and manuscript submission. C.B. was involved in imaging analysis and preparation of images. A.J. and J.B. per- formed the molecular analysis. P.T. performed the clinical evaluation of the patient. All authors reviewed and approved the final draft.
Funding
None declared.
Disclosures
None declared.
Informed Patient Consent for Publication
Signed informed consent was obtained directly from the patient.
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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