Society for Endocrinology
Bilateral and recurrent adrenocortical carcinoma in MEN1: a case report and review of the literature
Sophie Howarth 1,2, James MacFarlane1,2, August Palma1,2, Victoria J Stokes2, Benjamin Challis2, Joo Ern Ang3, Ines Harper4, Heok K Cheow1,4, John Tadross5,6, Ashley Shaw7, Mark Gurnell1,2 and Ruth T Casey®1,2,8
1Cambridge Endocrine Molecular Imaging Group, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
2Department of Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
3Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
4Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
5Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
6Medical Research Council Metabolic Diseases Unit, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK 7Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
8Department of Genetics, University of Cambridge, Cambridge, UK
Correspondence should be addressed to R T Casey: rc674@medschl.cam.ac.uk
Abstract
The autosomal dominant hereditary cancer syndrome multiple endocrine neoplasia type 1 (MEN1) is associated with an increased prevalence of both benign and malignant adrenal lesions. Although MEN1 mutations are implicated in around 7% of all adrenocortical carcinomas (ACCs), ACC itself is a rare occurrence within the MEN1 syndrome, and the majority of adrenal lesions are benign hyperplastic or adenomatous changes. Differentiating between a benign and malignant adrenal lesion in patients with MEN1 can be challenging, especially in the context of other primary cancers. We report the case of a 76-year-old lady with a genetic diagnosis of MEN1 who presented with a new 20 mm right adrenal nodule and progressive nodularity around the left adrenalectomy surgical bed, 9 years after adrenalectomy for left-sided ACC. Assessment of the right adrenal nodule was challenging in the presence of multiple other primary tumours, including neuroendocrine tumours, a renal lesion of uncertain significance, and a large intramuscular lipomatous lesion. We discuss how molecular imaging methods, including 18F-CETO PET-CT, assisted in making the diagnosis of suspected bilateral metachronous ACC with recurrence at her left adrenalectomy site. We review the cohort studies and case reports in the literature to discuss the association between MEN1 and ACC.
Learning points
· MEN1 is associated with an increased incidence of both benign and malignant adrenal lesions.
· The incidence of ACC among patients with MEN1 is between 0.5 and 6.9%, with a female predisposition.
· Bilateral ACC is rare in patients with MEN1 and in the wider ACC population.
· Positron emission tomography (PET) scanning using molecular tracers that bind to steroidogenic enzymes can identify whether lesions are adrenocortical in origin and has an emerging role in the diagnosis of indeterminate adrenal lesions, particularly in the presence of other primary cancers.
Keywords: adrenocortical carcinoma; ACC; MEN1
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Background
It is known that between 5 and 10% of all adrenocortical carcinomas (ACC) will be associated with a hereditary cancer syndrome such as Li-Fraumeni, Lynch syndrome, or multiple endocrine neoplasia type 1 (MEN1) (1, 2, 3). Classically associated with pituitary, parathyroid, and pancreatic tumours, the autosomal dominant MEN1 syndrome is also associated with an increased incidence of both benign and malignant adrenal lesions. ACC is a rare cancer both in the general population, where the prevalence sits between 0.5 and 2 per million per year (4), and within the MEN1 syndrome. However, around 20-30% of patients will have metastatic disease at presentation (4, 5), and the overall median survival of all ACC patients remains low at 3-4 years (6). The ENSAT staging system can be used to predict cancer- specific survival rates, with the mainstay of treatment for high-risk localised (ENSAT stage III) or metastatic disease (ENSAT stage IV) being mitotane therapy with possible addition of systemic chemotherapy regimens (6).
A significant proportion of patients with MEN1 (10-55%) will have abnormal adrenal glands on imaging (7, 8, 9, 10, 11, 12, 13), which is most commonly hyperplasia or benign adenomas rather than ACC (14). Furthermore, for lesions which have indeterminate or suspicious radiological features, establishing whether a lesion is of adrenal origin or a secondary metastasis can be challenging in the context of other primary cancers. Even once phaeochromocytoma has been excluded, the biopsy of indeterminate adrenal lesions is generally not recommended due to a low sensitivity for diagnosis of ACC and the risk of adrenal cancer seeding (15, 16). There is an emerging role for positron emission tomography (PET) using molecular tracers that bind to steroidogenic enzymes, such as 11C-metomidate and 18F-CETO, to identify whether lesions are adrenocortical in origin.
We present a patient with a complex history of MEN1-associated disease who developed an indeterminate 20 mm right adrenal nodule 9 years after a left adrenalectomy for ACC and discuss how molecular imaging was key in the assessment of this nodule.
Case presentation
A 76-year-old lady undergoing regular computed tomography (CT) surveillance following treatment for a left-sided ACC presented with a 20 mm, steadily enlarging, right adrenal nodule and progressive nodularity around her left adrenalectomy bed.
The patient underwent a left adrenalectomy 9 years previously for an incidentally discovered 45 mm left
adrenal nodule, which had been confirmed as an adrenocortical carcinoma on histopathological examination. Modified Weiss score was 6-7, Ki-67 was low at 1%, and there was local infiltration of the tumour into the adjacent peri-adrenal adipose tissue and venous system, giving the lesion a pT3 classification. The nodule stained diffusely for CYP11B1, which was in keeping with her pre-operative biochemical assessment, which showed mild biochemical hypercortisolism (inadequate suppression on 1 mg overnight dexamethasone suppression test of 98 nmol/L (reference range <50 nmol/L) and a suppressed DHEAS of <0.4 umol/L (0.4-4.9 umol/L)). Her ENSAT stage was III, and adjuvant mitotane therapy was commenced but was associated with unacceptable adverse effects, including extreme fatigue and nausea, prompting early cessation after 22 months of treatment with mitotane levels in therapeutic range. The patient had persistent adrenal insufficiency off mitotane and continued hydrocortisone replacement. She was monitored with serial CT scans during the following 7-year period with a total of 9 years’ progression-free survival from her surgery.
Her past medical history was complex. She had been diagnosed with a prolactinoma in her 20s, which was managed medically with bromocriptine, followed by hyperparathyroidism in her 30s, for which she underwent a total parathyroidectomy showing multiple gland hyperplasia. In her 40s, genetic testing confirmed a diagnosis of MEN1, and cascade testing was positive in two of her siblings and one of her children. She was diagnosed with type 2 diabetes in her 50s, which was managed with a mixed insulin regime alongside metformin. She had recurrent episodes of choledocholithiasis, and imaging work-up during one of these episodes had identified both the left adrenal nodule, which transpired to be ACC, alongside multiple lung nodules. She underwent CT-guided biopsy of her lung nodules, which revealed well-differentiated neuroendocrine tumour with MIB-1 index <1% and TTF1 staining indicative of diffuse intrapulmonary neuroendocrine carcinoma of the lung (DIPNEC). The lung nodules were not octreotide avid, and serial 5HIAA measurements were normal. In the following years, endoscopic ultrasound investigations revealed multiple pancreatic nodules, with fine needle aspirate confirming well-differentiated neuroendocrine tumour (MIB-1 index of <5%), and she was diagnosed with non- functioning pancreatic neuroendocrine tumours (pNETs) in addition to her DIPNEC. CT surveillance for her multiple tumours revealed other incidental findings, including a 12 mm stable right-sided renal lesion of uncertain significance, a stable 100 mm intramuscular lipoma in her left thigh, and an enlarging octreotide-avid mediastinal mass, which was presumed to be a thymic neuroendocrine tumour.
The nodularity at her left adrenalectomy bed was felt to be a recurrence of her previous ACC, but the new right adrenal
nodule posed a diagnostic challenge in the context of her multiple primary tumours and the high prevalence of benign adrenal nodules or hyperplasia in MEN1.
Investigation
The right adrenal nodule had not been previously reported on her surveillance scans, but retrospective review of her imaging revealed it had measured 9 mm the year before.
Dedicated adrenal protocol CT characterised the nodule as indeterminate, with unenhanced attenuation of 22 HU. The nodule was 69 HU on portal venous scan and 38 HU on delayed phase scan, giving an absolute washout of 66% and a relative washout of 45%.
Overnight dexamethasone test and DHEAS were not repeated, but she remained on physiological hydrocortisone doses with no cushingoid features,
normal electrolytes, and normal blood pressure. Plasma metanephrines were in the normal range. Three repeat urine steroid profiles taken over a 12-month period showed changes associated with hydrocortisone use only and no relative increase in ACC markers.
18F-FDG PET-CT was performed to aid differentiation between benign disease and malignancy based on metabolic activity. The right adrenal lesion was highly 18F-FDG avid, with moderate avidity in the nodularity in her left adrenalectomy bed and lung, thymic, and pancreatic neuroendocrine tumours. Subsequent 18F-CETO PET-MR showed a CETO avid right adrenal nodule and left adrenalectomy bed, with no other CETO avid disease seen in the rest of the body (Fig. 1).
The combined FDG and CETO avidity provided molecular imaging suspicion for a malignant right adrenocortical lesion, in addition to ACC recurrence at her left adrenalectomy bed.
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Treatment
The prospect of repeat surgical intervention or restarting systemic therapy was discussed with the patient, who opted for conservative management initially.
Outcome and follow-up
Repeat CT surveillance 6 months later showed new, evolving multifocal areas of low density in her liver with ongoing enlargement of her right adrenal nodule to 27 mm (Fig. 2). Ultrasound-guided biopsy of an 8 mm segment 8 liver lesion confirmed metastatic ACC, with Ki-67 index of 30% and scanty CYP11B1 immunostaining (Figs 2 and 3). 18F-CETO PET-CT was repeated and demonstrated additional disease in a left para-aortic node, high uptake in her liver lesions (including the
biopsied lesion), the known avid right adrenal lesion, and avid left adrenalectomy bed nodularity. A fourth urine steroid profile was taken at this time, showing an increase in the DHEA metabolite androstenetriol, which, on retrospective evaluation of the previous urine steroid profiles, was noted to be steadily rising from 39 µg/24 h to 896 µg/24 h over a 13-month period. There was no increase in other ACC markers.
A shared decision was made with the patient to recommence mitotane with concomitant addition of systemic combination chemotherapy.
Discussion
We report a complex case of bilateral and recurrent ACC in a patient with MEN1 and multiple other primary tumours, including DIPNEC, non-functioning pNETs, a
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Left adrenalectomy
CYP11B1
MIB-1
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Biopsied liver metastasis
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presumed thymic NET, a renal lesion of uncertain significance, and a large intramuscular lipomatous lesion.
Mutations in the MEN1 gene are significantly enriched in ACC, being found in ~7% of sequenced tumours (3). Other frequently mutated genes include TP53, ZNRF3, CDKN2A, CTNNB1, TERT, and PRKAR1A (3). Germline variants of implicated genes are seen in other hereditary cancer syndromes, including Li-Fraumeni (TP53), Beckwith- Wiedemann (IGF2), Lynch syndrome (MLH1, MSH2, MSH6, or PMS2) and Carney complex (PRKAR1A). Inactivating mutations in the MEN1 gene, coding for the tumour suppressor gene menin, predispose to tumourigenesis through dysregulation of the WNT/B-catenin signalling pathway and chromatin remodelling (2, 3).
A limitation of this report is that we cannot be certain whether the right ACC represented a metachronous second ACC or a metastasis from her left-sided ACC. However, ACCs are known to preferentially metastasise to the lymph nodes, liver, lung, and bone rather than the contralateral adrenal (5). Furthermore, her right adrenal nodule was identifiable on CT 2 years before the development of her liver and nodal metastases.
A literature search was performed on PubMed using the terms ‘ACC’ and ‘MEN1’. Articles were included in the review if they reported an existing diagnosis of MEN1 by genetic testing or by clinical diagnostic criteria.
Observational studies of patients with MEN1 report an incidence of ACC between 0.5 and 6.9%, significantly higher than in the general population (7, 8, 9, 10, 11, 12, 13). The largest cohort study, a retrospective analysis of 715 MEN1 patients in the French/Belgian multicentre Group d’etude des Tumeurs Endocrines database, reported an incidence of 1.4%, with ten ACCs in eight patients - one patient having two distinct ACCs within the same adrenal gland and one patient having
bilateral ACCs. Among the 715 patients, adrenal lesions >10 mm were seen in 10.1%, and of these lesions 13.8% were ACC, significantly higher than in their comparator cohort of 144 adrenal incidentaloma patients, among whom the incidence of ACC was 1.3% (7). A further retrospective American single-centre study of 382 patients had two cases of ACC, giving an overall incidence of 0.5% (13). Wang et al. reported an incidence of 1.5% in their Chinese cohort of 121 patients (9), and Febrero et al. reported an incidence of 1.9% (n = 2) in their Spanish cohort of 105 patients (8). Some smaller cohort studies have reported higher incidence of ACC in MEN1 patients between 2.6 and 6.9% (10, 11, 12). It is not clear whether the prognosis of ACC in MEN1 differs to those without MEN1, though Wang et al. reported worse prognosis with higher ENSAT stage, larger tumour size, and younger age (9).
Case reports of ACC in patients with MEN1 are summarised in Table 1. Females appear to be more commonly affected, in keeping with what is known about ACCs in the wider population (5). There does not appear to be an association between a particular MEN1 variant type (e.g. truncating versus missense) in either the reported case studies or genomic studies of the wider population (2, 3), though the numbers reported are small.
Bilateral lesions are a rare occurrence in ACC, with a frequency of 1.1% in a large retrospective American study of 3,982 ACC patients (5). Several case reports of synchronous or metachronous bilateral ACC also exist, but these reports do not mention an existing or subsequently diagnosed familial cancer syndrome (17, 18, 19, 20, 21, 22, 23, 24, 25, 26). Two cases of bilateral ACC in patients with MEN1 have been reported (7, 27). One 32-year-old female patient with a truncating mutation in exon 5, reported in the multicentre Group d’etude des Tumeurs Endocrines cohort, underwent a bilateral adrenalectomy for a 2.8 cm left-sided lesion and concurrent 2.5 cm
| Author | Age | Sex | CT/MRI findings* | Hormonal secretion | Metastatic disease at diagnosis | Intervention | Histopathological diagnosis | Genetic mutation | Other MEN1 associated disease | Adjuvant therapy | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Yang et al. (29) | 49 | F | Left: 87 mm | Cortisol | N | Left adrenalectomy, distal pancreatectomy | Mucinous ACC with capsular invasion; Weiss 3; Ki-67 15% | Exon 2; c.333_c.334 insT | PHPT; pNET | None | Postoperative abscess and intestinal obstruction, death from sepsis |
| Green et al. (30) | 66 | F | Right: 60 mm, HU > 20 | Cortisol | Y; lung | Right adrenalectomy | ACC arising in peri- adrenal adipose tissue; Weiss 5; Ki-67 15% | Performed; mutation not reported | pNET; PHPT | Mitotane | Stable at 2 years post- diagnosis |
| Parisien-La Salle et al. (31) | 48 | F | Right: 80 mm complex lesion Left: 18mm | Aldosterone# | N | Right adrenalectomy | 4 cm ACC with capsular invasion; two major LWB criteria; Ki-67 10%. | Exon 10; c.1556delC; p.Pro519fs | PHPT; AA (left) | None | 8 years recurrence-free, stable left adrenal adenoma |
| Concurrent 2.3 cm adenoma | |||||||||||
| Basheer et al. (32) | 62 | F | Left: size not reported | None | Y; liver, peritoneum+ | Not reported | ACC; Weiss not reported; Ki-67 2% | Performed; mutation not reported | AA (right); PHPT; pNET+ | Not reported | Not reported |
| Kim et al. (33) | 3 | F | Left: 61 mm | Androgens | N | Left adrenalectomy | ACC with venous invasion; 1 major LWB criteria; Ki-67 not reported | c.1298_1299delinsG; p.Pro433Argfs*17 | None | None | Not reported |
| Harada | 68 | F | Right: 70 mm, 32 HU | Cortisol; aldosterone | N | Right | Myxoid variant ACC with venous and capsular invasion; Weiss 7; Ki-67 21% | Genetic analysis not | pNET; NFPA, BC; PHPT | Mitotane | Developed liver metastases 14 weeks after surgery, death from liver and renal failure at 24 weeks post operatively |
| et al. (34) | adrenalectomy, nephrectomy, distal pancreatectomy | performed | |||||||||
| Ohara et al. (35) | 53 | F | Left: 40 mm | Cortisol | N | Left adrenalectomy | ACC with capsular invasion; Weiss 6; Ki- 67 8% | Exon 3; p.GIn209x | PHPT; AA (right); pNET | None | Developed liver metastases 6 months post adrenalectomy, mitotane started for metastatic disease |
| Kharb et al. | 43 | F | Right: 44 mm | Cortisol; androgens | Y; aortocaval | Left adrenalectomy and aortocaval lymph node excision | ACC; Weiss not reported; Ki-67 not reported | Genetic analysis not performed | PHPT; pNET | Chemotherapy (unspecified) | No follow up reported |
| (36) | lymph node | ||||||||||
| Haase et al. (37) | 53 | F | Right: 120 mm | Cortisol | N | Right adrenalectomy | ACC with lymphatic, vascular and capsular invasion; Weiss 3; Ki-67 not reported | Exon 9; c.1327C>A; p.Ser443Tyr | PHPT; pNET | Mitotane | Recurrence 3 months post adrenalectomy - right adrenal lesion and two left adrenal lesions. Repeat right adrenalectomy, death from thromboembolism post-operatively |
| Griniatsos et al. (27) | 31 | F | Right: 80 mm Left: 75 mm | Cortisol; androgens | N | Bilateral adrenalectomy, nephrectomy of ectopic kidney, distal pancreatectomy and splenectomy | Bilateral ACC; Weiss not reported; Ki-67 not reported | Exon 2; p. Glu45Val | PHPT; PRL; pNET | None | Not reported |
Abbreviations: PHPT, primary hyperparathyroidism; pNET, pancreatic neuroendocrine tumour; NFPA, non-functioning pituitary adenoma; BC, breast cancer; AA, adrenal adenoma; LWB, Lin-Weiss-Bisceglia criteria; PRL, prolactinoma. *Largest diameter reported. HU given where reported. +Based on 68Ga-DOTANOC PET/CT imaging and elevated PTH levels. * Aldosterone secretion from adenoma based on immunohistochemical staining.
right-sided lesion with Weiss scores 3 and 5, respectively (7). A second case report presented a 31-years-old female with a novel germline mutation (p.E45V) in exon 2 of the MEN1 gene, who was found to have bilateral adrenal tumours (right adrenal 8.0 × 4.5 cm and left adrenal 7.5 x 5.5 cm) associated with glucocorticoid and androgen excess, with bilateral ACC confirmed on histopathology (27). To our knowledge, this is the third case of bilateral ACC in MEN1 reported in the literature.
In our case, multiple urine steroid profiles taken during the assessment did not show any increase in markers of ACC, but a steady rise in the DHEAS metabolite androstenetriol was noted. Given that urine steroid profile is validated for adrenal lesions >4 cm, the results in this case may reflect the smaller size of the right ACC and recurrence at the left adrenalectomy bed (28).
This case demonstrates the utility of molecular imaging methods such as 11C-metomidate PET-CT or 18F-CETO PET-CT in the diagnostic assessment of adrenocortical lesions. These utilise radiolabelled tracers binding to the adrenocortical steroidogenic enzymes CYP11B1 and CYP11B2 to identify lesions of adrenocortical origin. A potential pitfall may arise in de-differentiated ACCs with disordered steroidogenesis, where CYP11B1 and CYP11B2 expression may be lost. Of note, our patient had diffuse CYP11B1 expression in her primary left ACC, but only scanty expression in her later liver metastasis (Fig. 3). Nevertheless, the biopsied liver metastasis was avid on 18F-CETO PET-CT.
Bilateral adrenocortical carcinoma is a rare phenomenon, and ACC is a rare manifestation of MEN1. Recurrent surveillance and intervention are burdensome for patients with familial cancer syndromes, and priority should be given to the least invasive investigations which yield the most helpful information. Establishing the nature of an adrenal lesion in a patient with multiple existing primary cancers is challenging and can be assisted by molecular imaging techniques.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work was supported by the NIHR Cambridge Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department.
Author contribution statement
SH, RC, and JM authored the manuscript and designed the figures. AP, VS, BC, IH, JA, JT, AS, and HK were involved in the diagnosis and care of the patient. All authors reviewed and approved the manuscript.
Patient consent
Informed consent for publication was obtained from the patient.
References
1 Petr EJ & Else T. Adrenocortical carcinoma (ACC): when and why should we consider germline testing? Presse Med 2018 47 e119-e125. (https://doi.org/10.1016/j.lpm.2018.07.004)
2 Assié G, Letouzé E, Fassnacht M, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 2014 46 607-612. (https://doi.org/10.1038/ng.2953)
3 Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 2016 29 723-736. (https://doi.org/10.1016/j.ccell.2016.04.002)
4 Aspinall SR, Imisairi A, Bliss RD, et al. How is adrenocortical cancer being managed in the UK? Ann R Coll Surg Engl 2009 91 489-493. (https://doi.org/10.1308/003588409x432284)
5 Bilimoria KY, Shen WT, Elaraj D, et al. Adrenocortical carcinoma in the United States. Cancer 2008 113 3130-3136. (https://doi.org/10.1002/cncr.23886)
6 Fassnacht M, Dekkers OM, Else T, et al. European society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the european network for the study of adrenal tumors. Eur J Endocrinol 2018 179 G1-G46. (https://doi.org/10.1530/EJE-18-0608)
7 Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’étude des Tumeurs Endocrines database. Eur J Endocrinol 2012 166 269-279. (https://doi.org/10.1530/eje-11-0679)
8 Febrero B, Segura P, Ruiz-Manzanera JJ, et al. Uncommon tumors in multiple endocrine neoplasia (MEN) type 1: do they have a relationship with the prognosis of these patients? J Endocrinol Investig 2021 44 1327-1330. (https://doi.org/10.1007/s40618-020-01414-2)
9 Wang W, Han R, Ye L, et al. Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature. Endocr Connect 2019 8 230-238. (https://doi.org/10.1530/ec-18-0526)
10 Waldmann J, Bartsch DK, Kann PH, et al. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch Surg 2007 392 437-443. (https://doi.org/10.1007/s00423-006-0124-7)
11 Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 2002 26 891-896. (https://doi.org/10.1007/s00268-002-6492-4)
12 Skogseid B, Rastad J, Gobl A, et al. Adrenal lesion in multiple endocrine neoplasia type 1. Surgery 1995 118 1077-1082. (https://doi.org/10.1016/s0039-6060(05)80117-5)
13 Clemente-Gutierrez U, Pieterman CRC, Lui MS, et al. Beyond the three P’s: adrenal involvement in MEN1. Endocr Relat Cancer 2024 31 e230162. (https://doi.org/10.1530/erc-23-0162)
14 Schaefer S, Shipotko M, Meyer S, et al. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Eur J Endocrino/ 2008 158 699-704. (https://doi.org/10.1530/EJE-07-0635)
15 Fassnacht M, Tsagarakis S, Terzolo M, et al. European society of endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the european network
for the study of adrenal tumors. Eur J Endocrino/ 2023 189 G1-G42. (https://doi.org/10.1093/ejendo/lvad066)
16 Bancos I, Tamhane S, Shah M, et al. Diagnosis of endocrine disease: the diagnostic performance of adrenal biopsy: a systematic review and meta-analysis. Eur J Endocrino/ 2016 175 R65-R80. (https://doi.org/10.1530/eje-16-0297)
17 Hara I, Sakamoto Y, Kanomata N, et al. Long-term survival after bilateral adrenalectomy for metachronous adrenocortical cancer. Int J Urol 2004 11 1127-1129. (https://doi.org/10.1111/j.1442-2042.2004.00963.x)
18 Pusantisampan T, Sangkhathat S, Kayasut K, et al. Cushing’s syndrome in an infant secondary to malignant adrenocortical tumors with somatic mutation of beta-catenin. Pediatr Dev Pathol 2010 13 238-242. (https://doi.org/10.2350/09-07-0683-cr.1)
19 Kim DG, Kim SD, Cha JS, et al. Unusual presentation of bilateral adrenocortical carcinoma mimicking adrenal metastasis. Korean J Urol 2011 52 715-717. (https://doi.org/10.4111/kju.2011.52.10.715)
20 Polistina FA, Farruggio A, Gasparin P, et al. Spontaneously metachronous ruptures of adrenocortical carcinoma and its contralateral adrenal metastasis. Int Cancer Conf J 2015 5 90-97. (https://doi.org/10.1007/s13691-015-0235-5)
21 Ishikawa N, Nagase M, Takami S, et al. A case report of bilateral sarcomatoid carcinoma of adrenal glands with adrenal insufficiency. Int J Surg Pathol 2016 24 743-748. (https://doi.org/10.1177/1066896916657589)
22 Turhan Iyidir O, Cerit ET, Özkan Ç, et al. A case report of bilateral adrenal sarcomatoid carcinoma. Case Rep Surg 2016 2016 1-4. (https://doi.org/10.1155/2016/3768258)
23 Daga G, Sharma S & Mittal V. Bilateral aldosterone-producing adrenocortical carcinoma: a rare entity. Indian J Surg Oncol 2017 8 88-90. (https://doi.org/10.1007/s13193-016-0563-8)
24 Nikoleishvili D, Koberidze G, Kutateladze M, et al. Bilateral adrenocortical carcinoma: case report and review of literature. Georgian Med News 2018 274 19-24. (https://pubmed.ncbi.nlm.nih.gov/29461221/)
25 Aggarwal A, Verma A, Roy A, et al. Bilateral adrenocortical carcinoma presenting as acute adrenal insufficiency. Eur Endocrinol 2020 16 172-174. (https://doi.org/10.17925/ee.2020.16.2.172)
26 Chen H, Dai J, Gao F, et al. Right adrenocortical carcinoma coexisting with left adrenal sarcomatoid carcinoma on FDG PET/CT. Clin Nucl Med 2023 48 E503-E505. (https://doi.org/10.1097/rlu.0000000000004797)
27 Griniatsos JE, Dimitriou N, Zilos A, et al. Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1
(MEN1) and a novel mutation in the MEN1 gene. World J Surg Oncol 2011 9 6. (https://doi.org/10.1186/1477-7819-9-6)
28 Bancos I, Taylor AE, Chortis V, et al. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet Diabetes Endocrinol 2020 8 773-781. (https://doi.org/10.1016/s2213-8587(20)30218-7)
29 Yang M, Li S & Zhong XW. Multiple endocrine neoplasia type 1 with adrenal cortical adrenocortical carcinoma: a 25-year follow-up and family report. JCEM Case Rep 2025 3 luae248. (https://doi.org/10.1210/jcemcr/luae248)
30 Green D, Richards K, Doyle B, et al. Extra-adrenal adrenocortical cancer associated with multiple endocrine neoplasia type 1. Endocrinol Diabetes Metab Case Rep 2024 2024 0023-0068. (https://doi.org/10.1530/edm-23-0068)
31 Parisien-La Salle S, Corbeil G, El-Haffaf Z, et al. Genetic dissection of primary aldosteronism in a patient with MEN1 and ipsilateral adrenocortical carcinoma and adenoma. J Clin Endocrinol Metab 2023 108 26-32. (https://pubmed.ncbi.nlm.nih.gov/36179244/)
32 Basheer S, Ratheesan R, Sarma M, et al. 68Ga-DOTANOC PET/CT in multiple endocrine neoplasia 1 with associated adrenocortical carcinoma. Clin Nucl Med 2022 47 E389-E392. (https://doi.org/10.1097/rlu.0000000000004102)
33 Kim SE, Lee NY, Cho WK, et al. Adrenocortical carcinoma and a sporadic MEN1 mutation in a 3-year-old girl: a case report. Ann Pediatr Endocrinol Metab 2022 27 315-319. (https://doi.org/10.6065/apem.2142100.050)
34 Harada K, Yasuda M, Hasegawa K, et al. A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Endocr J 2019 66 739-744. (https://doi.org/10.1507/endocrj.ej19-0067)
35 Ohara N, Kaneko M, Ikeda M, et al. Lung adenocarcinoma and adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Respir Med Case Rep 2017 20 77-81. (https://doi.org/10.1016/j.rmcr.2016.12.002)
36 Kharb S, Pandit A, Gundgurthi A, et al. Hidden diagnosis of multiple endocrine neoplasia-1 unraveled during workup of virilization caused by adrenocortical carcinoma. Indian J Endocrinol Metab 2013 17 514. (https://doi.org/10.4103/2230-8210.111672)
37 Haase M, Anlauf M, Schott M, et al. A new mutation in the menin gene causes the multiple endocrine neoplasia type 1 syndrome with adrenocortical carcinoma. Endocrine 2011 39 153-159. (https://doi.org/10.1007/s12020-010-9424-3)