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Atypical clinical presentation of oncocytic adrenocortical carcinoma with decompensated metabolic syndrome and psychotic outbreak
Bastien Picut İD ,
1 Jean-Baptiste Dubuis İD
2 Marco Stefano Demarchi,3 ,
Ian Fournier İD 1,4
1Department of General & Visceral Surgery, Valais Hospital, Sion, Switzerland 2Department of Thoracic and Endocrine Surgery, Geneva University Hospitals, Geneve, Switzerland 3Department of Thoracic and Endocrine Surgery and Faculty of Medicine, Geneva University Hospitals, Geneve, Switzerland 4Department of Visceral Surgery, Geneva University Hospitals, Geneve, Switzerland
Correspondence to
Dr Bastien Picut; bastien.picut@gmail.com
Accepted 27 December 2024
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C BMJ Publishing Group Limited 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
To cite: Picut B, Dubuis J-B, Demarchi MS, et al. BMJ Case Rep 2025;18:e262948. doi:10.1136/bcr-2024- 262948
SUMMARY
Adrenal incidentalomas, mostly adrenal adenomas, affect 3%-10% of the global population. Adrenocortical carcinoma (ACC) is rare, with an incidence of 0.7-2 cases per million. Adrenocortical oncocytic neoplasms (ACONs) account for about 10% of ACC cases, often discovered incidentally, with 17-34% being functionally active.
We report a case of a woman in her 60s with treatment- resistant hypertension, diabetes and psychotic delirium. Imaging revealed a 6 cm left adrenal mass with marginally elevated metanephrines. Laparoscopic adrenalectomy was performed. Histology confirmed ACON. Positive margins necessitated adjuvant chemotherapy and radiotherapy. Postoperatively, psychiatric symptoms and hypertension resolved, indicating the tumour’s secretory nature.
This case highlights the diverse ACONs hormonal secretions, leading to complex clinical presentations, including metabolic and psychiatric symptoms. ACONs secretory nature may not be reflected in standard hormonal panels.
ACONs challenging diagnosis and management emphasise the need for a multidisciplinary approach and further research.
BACKGROUND
The fortuitous discovery of an adrenal mass is defined as an adrenal incidentaloma, which is very common, affecting 3%-10% of the global population, with most cases presenting as adrenal adenomas.1 In contrast, adrenocortical carci- noma (ACC) is a rare disease, with an estimated incidence of 0.7-2 cases per million annually.2 Adrenocortical oncocytic neoplasms (ACONs), constituting about 10% of the ACCs,3 are typically incidentally detected and literature regarding this pathology remains limited. Indeed, the hormonal activity of the ACONs is unclear: a systematic review by Kanitra et al found that 34% of ACONs were hormonally functional,4 which is in contrast with the results (17%) of Mearini et al’s system- atic review.3 These tumours predominantly affect females (66%) with an average age of 44 years and a median size of 80mm, often larger than other adrenal tumours. Most ACONs are left adrenal gland tumours (64%).4 The 5 years survival rate for malignant ACONs is reported to be 47%, with a recurrence rate of 16%, 80% of which occur within the first 5 years.4 Here, we present the case
of an ACON with an unusual presentation, discov- ered in the context of a decompensated metabolic syndrome and psychotic outbreak.
CASE PRESENTATION
We present the case of a woman in her 60s who was admitted due to decompensated metabolic syndrome. She exhibited symptoms of refractory arterial hypertension accompanied by dizziness, headache, asthenia and a weight gain of 20kg within a span of 6 months. Despite maximal anti- hypertensive therapy (amlodipine 10mg, lisinopril 20 mg, métoprolol 50mg, aldactone 25 mg, all PO), her systolic blood pressure remained around 160mm Hg. The investigation revealed an onset of type 2 diabetes, requiring insulin immediately, and mixed hyperlipidemia associated with hypo- kalaemia and hypernatraemia. While hospitalised under geriatric care, she experienced a psychotic breakdown, characterised by persecutory delirium, non-critical visual hallucinations and mistrust of contacts associated with anxiety, particularly fear of transmitting SARS-CoV2 as she believed herself to be the origin of the pandemic. She was initially treated, after the exclusion of a cerebral lesion, with haloperidol (1 mg three times per day Per Os (PO)) and clomethiazole (192 mg two times per day PO as needed). Due to extreme agitation involving self-harm, she was transferred to a psychogeriatric unit. During her stay, she received care through a multidisciplinary approach that encompassed a hypostimulant framework, psychiatric and psycho- therapeutic treatment. Behavioural disorders improved, but delusions persisted and were associ- ated with disabling anxiety and a tendency towards social withdrawal.
Liver tests were abnormal with gamma- glutamyltranspeptidase levels at 1749U/L, total bili- rubin at 17.3 umol/L, ALAT 118U/L, ASAT 85 U/L, alkaline phosphatase 74 U/L, as well as hypernatraemia at 149 mmol/L. Calcaemia and ammonia levels were normal, at 2.31 mmol/L and 36 umol/L respectively.
Concurrently, she experienced dysuria without fever, asthenia, and intermittent sweating, prompting her readmission to an internal medicine department for further investigation.
Her medical history is relevant for hypertension, morbid obesity and unstaged heart failure. She did not use alcohol, tobacco or other substances. She had a surgical history of appendicectomy 10 years earlier and two C-sections 40 years ago. Prior to admis- sion, her medications included olmesartan 20/25 mg,
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hydrochlorothiazide 10mg, verapamil 120mg, acetylsalicylic acid 100mg and bezafibrate 400mg, all PO. Neither she nor her family have a history of psychiatric disorders, and her family has no notable diseases.
Initial physical examination revealed a blood pressure of 189/105 mm Hg, a heart rate of 104/min, oxygen saturation of 99% on room air, and a temperature of 37.1°. Her body mass index was 46.7 kg/m2.
She was alert and fully oriented to name, place, time and purpose. She had anxiety. She had regular tachycardia, normal heart sounds, clear bilateral chest auscultation and a distended abdomen with mild
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epigastric tenderness. She had bilateral lower limb oedemas up to knee level. Skin examination was unremarkable.
INVESTIGATIONS
Urine analysis revealed proteinuria, ketonuria, urobilinogen and haematuria. Hepatitis A-B-C-E, HIV, EBV, CMV serology and a complete autoimmune panel were negative. Aldosterone renin ratio was normal (0.003) with renin 27.8 mUl/L and aldosterone 0.08 nmol/L.
Further functional assessments including estradiol (333 pmol/L), progesterone (0.39 nmol/L), 17-OH-progesterone (14.1 nmol/L), androstenedione (11.5 nmol/L), DHEAS (9.17 (0.26-6.68 umol/L) and cortisoluria (53 nmol/24hours) were normal. Only DHEAS (9.17 umol/L) and urinary catecholamines, including metaneph- rine (1283 nmol/24 hours), normetanephrine (4218 nmol/24 hours), methoxytyramine (2107 nmol/24 hours), were marginally increased. ACTH, GnRH, LH and FSH were not assessed.
Following initial evaluation, an ultrasound was performed, revealing a large bilobed retropancreatic mass facing the left kidney and para-aortic region. Subsequent abdominal CT imaging (figure 1) confirmed the bilobed left adrenal mass, measuring 8×5cm and 1.8×2.2cm, which was vascularised without calcifications. The CT scan ruled out the presence of any locoregional or distant spreading of the disease.
DIFFERENTIAL DIAGNOSIS
Regarding the liver test abnormalities, we ruled out haemochroma- tosis due to the absence of significant hyperferritinaemia, as well as viral causes with negative hepatitis serologies. Autoimmune condi- tions, such as primary biliary cirrhosis, primary cholangitis and autoimmune hepatitis, were also excluded following a negative auto- immune work-up. A liver biopsy confirmed histological evidence of NASH, consistent with an unbalanced metabolic syndrome likely related to diabetes and dyslipidaemia.
The differential diagnosis initially included a secretory adenoma, but this was deemed unlikely based on radiological findings and normal renin, aldosterone and cortisol levels. Although the imaging did not reveal a primary neoplasm, a neoplastic origin (either primary or secondary) could not be completely ruled out. A pheochromocy- toma was also considered, supported by radiological features and
elevated urinary metanephrines, suggesting the secretion of catechol- amine precursors. No other causes for the elevated urinary catechol- amines were identified.
TREATMENT
Prior to the intervention, the patient was medically managed with haloperidol (1mg PO three times per day) and clomethiazole (192mg PO two times per day as needed) for psychiatric decompen- sation; metformin 500mg PO three times per day, linagliptin 5 mg PO and insulin glargine 30U SC for diabetes; metoprolol 50mg, spironolactone 25 mg, lisinopril 20mg and doxazosine 4mg all PO for hypertension.
Due to a marginal increase in plasmatic and urinary meta- nephrines, with subsequent normalisation of her blood pressure, she was treated as if it was a pheochromocytoma with doxazosin.
This case was discussed during our institution’s tumour board meeting, and we opted for surgery as the first course of action. She underwent laparoscopic left adrenalectomy without encoun- tering intraoperative complications. The patient required adrenergic support until postoperative day four. Additionally, all antihyperten- sive therapies were discontinued except for the beta-blocker. Due to the circumstances caused by the pandemic, she was transferred to another clinic and subsequently discharged home.
OUTCOME AND FOLLOW-UP
Subsequent histology results revealed an oncocytic adrenocortical carcinoma, staged as pT2 pN0 R1, with incomplete resection on the non-peritonealised side (R1). The mass fulfilled the Lin-Weiss- Bisceglia criteria for malignant ACONs (figures 2 and 3). Tumour cells were positive for synaptophysin, inhibin, calretinin, Melan-A and CD56, which confirmed the adrenal origin of the mass, but nega- tive for chromogranin, protein S100, KWS, HepPar1, AFP, TTF1, CK7, CK20, HMB45, SOX10, thyroglobulin and PAX8, consistent with a non-secreting mass. The Ki67 proliferation index was 10%.
CT of the abdomen 2months later showed the post-resection status of the left adrenal carcinoma, with a fleshy infiltrative appear- ance measuring 2.8x2cm bordering the pancreatic tail, the left renal medial side, and the coeliac trunk, suspected to be a tumour remnant. Nodular thickening of the peritoneum at the level of the left paracolic gutter evokes the beginning of dissemination requiring monitoring in the context.
Adjuvant chemotherapy with mitotane was initiated alongside concomitant radiotherapy targeted at the resection area. Glucocor- ticoid replacement therapy was introduced to prevent adrenal insuf- ficiency. The patient recovered fully from her psychiatric condition.
DISCUSSION
In our case, the diagnosis of ACON was atypical, as only 17%-34% of ACONs are functional.4 The tumour was identified in the context of a fully decompensated metabolic syndrome and psychotic decom- pensation. In contrast, 55% of patients with ACC present with symptoms related to adrenocortical hypersecretion, typically hyper- cortisolism combined with hyperandrogenism, while 30%-40% have symptoms due to tumour volume, and the remaining 10% are discovered incidentally.2
To our knowledge, this is the first ACON case described in the literature with such an atypical clinical presentation. The psychotic presentation of ACC has been described but, on a cortisol-secreting ACC as a part of Cushing’s syndrome.
Imaging plays a crucial role in distinguishing benign from poten- tially malignant adrenal masses. While CT and MRI cannot defin- itively identify ACONs, they can raise suspicion. Inhomogeneous lesions larger than 4cm or with a density of >20 Hounsfield units on CT are considered at higher risk of malignancy, making surgery
the preferred treatment option. In our case, imaging indicated malig- nancy, though it is not always reliable for differentiating subtypes of malignant tumours.4
Histological analysis remains the gold standard for diagnosing ACON. The Lin-Weiss-Bisceglia classification system, established in 2004, has replaced the original Weiss criteria. According to this system, ACONs are classified as malignant if they meet at least one primary criterion (eg, a mitotic rate of more than 50 mitoses per 50 high-power fields, atypical mitoses or venous invasion).4 Tumours with only minor criteria, such as size larger than 10cm, necrosis, sinusoidal or capsular invasion, are considered of uncertain malig- nant potential.6 If neither primary nor minor criteria are present, the tumour is classified as an oncocytic adrenal cortical adenoma.4
The European Network for the Study of Adrenal Tumours staging system is used to assess tumour stage.7 Surgical management should aim for complete resection without rupture of the adrenal capsule.8 For tumours larger than 6cm, the European Society of Endocri- nology recommends open adrenalectomy by an experienced adrenal surgeon. This threshold, also applied to suspected pheochromocy- tomas,9 is somewhat arbitrary, and the surgeon’s experience is crucial in the decision-making process.7 In our case, we performed left lapa- roscopic adrenalectomy via a transabdominal approach, which may have contributed to the R1 status of our resection.10
ACONs are a rare entity, typically only diagnosed through histo- logical examination. In most cases, they are non-secretory, with 68% of these tumours being non-functional, which often leads to delayed diagnosis and treatment.7 One limitation in our case was the delay in operative management due to an atypical presentation, including psychotic decompensation and metabolic syndrome, initially raising suspicion of Cushing’s syndrome caused by pheochromocytoma. This challenge was further compounded by the SARS-CoV-2 pandemic, which limited access to critical diagnostic tests like PET- CT, making timely diagnosis even more difficult.
Additionally, we could not conclusively determine whether the tumour was a pure non-secreting ACON. The clinical presen- tation resembled Cushing’s syndrome, and hypokalaemia could be attributed to vasospasm from secondary hyperaldosteronism. Due to the patient’s ongoing use of antihypertensive medications (B-blockers, spironolactone, calcium channel blockers and ACE inhibitors), we were unable to definitively assess the tumour’s aldo- sterone secretion. This may have affected the aldosterone-renin ratio, leading to a potentially false-negative assessment.11 A dexa- methasone suppression test, which is recommended for evaluating Cushing-like syndromes, was not performed due to the patient’s psychiatric condition.7 While a glucocorticoid precursor secreted by the tumour could explain the symptoms, we were unable to measure this. It is also important to note that standard hormonal panels may not fully exclude the secretory nature of adrenal masses, and steroid precursor analysis should be considered when clinical suspicion is high.12 In our case, we hypothesise that the tumour was secreting metanephrines, as evidenced by the fact that most of the antihyper- tensive therapy could be discontinued following surgical removal of the tumour. This suggests that the tumour’s secretion of metaneph- rines was likely contributing to the patient’s hypertensive state.
The rarity of ACONs and the limited available evidence under- scores the importance of a multidisciplinary approach to optimise patient care.13 As ACONs are a subtype of ACC, their clinical management generally follows the guidelines for ACC, particularly when considering the resection of tumours suspected to be malig- nant or hormone-secreting.
Due to the uncommon nature of ACONs, there is no standardised follow-up protocol. Accurate classification requires the expertise of a skilled pathologist, as the disease course can vary significantly. While oncocytomas and oncocytic neoplasms of uncertain malignant
Case report
potential tend to have favourable prognoses, Bottazzi et al have shown that ACONs carry a higher risk of local recurrence (5.1%), metastasis (3.7%), and mortality (30%).8 This highlights the neces- sity of long-term follow-up to detect disease progression.14
The follow-up of ACONs can be compared with other rare and aggressive adrenal neoplasms, such as leiomyosarcomas. Managing these conditions involves considering multiple factors-such as the patient’s age, sex, tumour size and extent of disease-to develop individualised monitoring strategies.14 This comprehensive approach is crucial to ensure appropriate long-term surveillance and optimise outcomes for patients with such rare tumours.
This case report underscores the critical importance of thoroughly evaluating adrenal incidentalomas, especially in the presence of metabolic disorders or unexplained hypertension. Prompt evalua- tion of patients with atypical symptoms, as observed in this case, in specialised facilities for comprehensive work-up and management is imperative to ensure accurate diagnosis and timely treatment tailored to individual patient needs.
Patient’s perspective
My blood pressure was too high, and I remember not being able to take it at home. So I went to see a substitute doctor because my GP was on holiday. As I explained to him, I could see in his eyes that he was making fun of me a little. Then he didn’t succeed either. He gave me some medicine and then he still couldn’t measure my blood pressure, so he referred me to an emergency. After that, I don’t remember much, except that I wondered what I was doing in a psychiatric hospital. It was a difficult time and my son told me that he didn’t recognise me in my behaviour. Then I met my surgeon, whom I trusted straight away. I thought I had a lump of fat, but he was able to tell me the diagnosis in a human way, always with a word of comfort. Then the operation went well, and I was soon back home with nursing help and physiotherapy sessions at home. I was followed up by my oncologist, endocrinologist and surgeon, which reassured me and helped me get outside. Indeed, I was afraid of going out and contracting covid again. Now, I only go out when I need to, because I’m not as resistant as I used to be, and I get tired quicker.
As I fully recovered from my psychiatric episode, I didn’t need any psychiatric follow-up, and psychotherapy was never an option. Finally, I’ve always been well surrounded by my husband, my son and the Lord. Without my faith and the Lord, I wouldn’t be here.
Learning points
The variable clinical presentation and lack of sensitivity and specificity of preoperative diagnostic modalities like imaging in an aggressive malignancy make adrenocortical oncocytic neoplasms a considerable challenge for clinicians.
A complete biological work-up, including a hormonal panel as well as steroid precursors in case of high clinical suspicion, is essential to establish an optimal treatment plan.
The best management care is a complete resection.
There are still no solid recommendations for adrenocortical oncocytic neoplasm management, making this entity an exciting topic for future research.
X Jean-Baptiste Dubuis @jbdubuis
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: BP and JBD. The following authors gave final approval of the manuscript: MSD and IF. Guarantor is IF.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained directly from patient(s). Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
ORCID iDs
Bastien Picut http://orcid.org/0009-0002-8950-2367
Jean-Baptiste Dubuis http://orcid.org/0009-0003-2651-718X lan Fournier http://orcid.org/0000-0001-8625-8587
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