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Adrenal cortical carcinoma - a case series and literature review of aggressive adrenal incidentalomas
Liesbeth Verlinde, Sam Kinet, Klaas Van Den Heede, Nele Brusselaers & Sam Van Slycke
To cite this article: Liesbeth Verlinde, Sam Kinet, Klaas Van Den Heede, Nele Brusselaers & Sam Van Slycke (2025) Adrenal cortical carcinoma - a case series and literature review of aggressive adrenal incidentalomas, Acta Chirurgica Belgica, 125:4, 202-210, DOI: 10.1080/00015458.2025.2506935
To link to this article: https://doi.org/10.1080/00015458.2025.2506935
Published online: 17 May 2025.
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CASE REPORT
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Adrenal cortical carcinoma - a case series and literature review of aggressive adrenal incidentalomas
Liesbeth Verlindea,b ID, Sam Kineta,b (D, Klaas Van Den Heedeb ID, Nele Brusselaersc,d,e and Sam Van Slyckeb,e,f İD
ID
aFaculty of Medicine, KU Leuven, Leuven, Belgium; bDepartment of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium; “Department of Microbiology, Tumour and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden; dGlobal Health Institute, University of Antwerp, Wilrijk, Belgium; eDepartment of Head and Skin, University Hospital Ghent, Ghent, Belgium; ‘Department of General Surgery, AZ Damiaan, Ostend, Belgium
ABSTRACT
Objective: Adrenal cortical carcinoma (ACC) is a rare and aggressive endocrine malignancy. Clinical symptoms are mainly related to excess hormone secretion. Hypercortisolism and virilisation are among the most common presentations.
Methods: We report a case series of five patients with ACC, three of which presented as adrenal incidentalomas. Additionally, a literature review on current diagnosis and management of ACC was performed.
Results: ACCs are often incidentally detected because of the liberal use of medical imaging. Management of ACC remains challenging, and the poor prognosis makes early diagnosis of crucial importance to increase chances of a better outcome. Biochemical evaluation should be performed to diagnose hormonally active tumours.
Conclusion: Surgery is the main and only potentially curative treatment option. Adjuvant treatment with mitotane may improve survival and is indicated for patients with a perceived high risk of recurrence. Aggressive cytotoxic therapy should be given to patients with an unfavourable prognosis.
ARTICLE HISTORY
Received 14 October 2023 Accepted 9 May 2025
KEYWORDS
Adrenal cortical carcinoma; incidentaloma; adrenalectomy; case series
Introduction
Adrenal cortical carcinoma (ACC) is a rare and aggres- sive tumour with an annual incidence of 0.5-2.0 cases per million per year [1,2]. Patients with ACC have a poor prognosis, with 5-year survival rates in between 16 and 47% [2]. In case of metastatic dis- ease, reported survival rates are even much lower, emphasizing the importance of early diagnosis [2,3]. Accompanying endocrine disturbances and tumour growth contribute to severe morbidity. Approximately two-thirds of all patients with ACC have hypersecret- ing tumours that produce glucocorticoids and/or androgens, and over one-third will exhibit Cushing’s syndrome due to hypercortisolism [4]. Widespread application of imaging has led to an increased inci- dental detection of asymptomatic and non-functioning ACCs [5,6]. The term ‘incidentaloma’ can refer to any incidental lesion (pituitary, thyroid, … ), but is most often used to denote an incidental finding of an adrenal lesion [7,8]. We report five cases of adreno- cortical carcinoma, three of which presented as an incidentaloma (Table 1).
Case 1
A 38-year-old woman was admitted to our surgery department for the evaluation of a right adrenal inci- dentaloma. Due to nausea with suspicion of symptom- atic cholecystolithiasis, an ultrasound scan was performed revealing an adrenal mass. The patient showed no signs of virilisation, weight loss or weight gain, headache, or hypertension. Vital signs were nor- mal and medical history revealed insulin-dependent diabetes. Clinical examination could not reveal obvious Cushingoid features. Blood tests showed suppressed serum adrenocorticotropic hormone (ACTH) (<3 ng/L, reference range: 7.2-63.0ng/L) with borderline cortisol levels (17.7 µg/dL, determined at 10pm, reference range: 6.2-18.0 µg/dL). Midnight salivary cortisol was elevated (6.60 µg/L, reference range: < 2.7µg/L). A 24-hour urine collection revealed a norepinephrine, cortisol, and creatinine content of 22 ug/day, 52.6 ug/day and 775 mg/day, respectively. These find- ings confirmed an autonomous adrenal production of glucocorticoids. Contrast-enhanced abdominal com- puted tomography (CT) revealed a spherical lesion
CONTACT Klaas Van Den Heede Hospital Aalst-Asse-Ninove, Moorselbaan 164, 9300 Aalst, Belgium @ 2025 The Royal Belgian Society for Surgery
| Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | |
|---|---|---|---|---|---|
| Demographics | |||||
| Gender | Female | Female | Male | Male | Female |
| Age at diagnosis | 38 | 67 | 84 | 71 | 56 |
| Presentation | Hirsutism Weight loss Back pain | ||||
| Incidentaloma | Incidentaloma Hirsutism | Fever Dyspnoea Urinary retention | Incidentaloma | ||
| Lab results | |||||
| Cortisol (µg/dL) | 17.7 | 22.6 | 15.5 | 16.6 | 21.2 |
| ACTH (ng/L) | <3 | / | 81.6 | / | 34.6 |
| DHEAS (µg/dL) | 384.0 | 607.4 | 1232.2 | 716.0 | / |
| Aldosterone (ng/L) | 130 | 152 | / | / | 79 |
| Confirmation of hypercortisolism | |||||
| Midnight salivary cortisol (µg/L) | 6.60 | / | / | / | / |
| One mg dexamethasone suppression test (µg/dL) | / | 3.7 | 1 | 2.2 | 1 |
| Urinalysis | |||||
| Free cortisol (µg/dL) | 87.7 | 29.8 | 4.9 | 4.1 | / |
| Metanephrine (µg/L) | 34 | 288 | 22 | 47 | 92 |
| Normetanephrine (µg/L) | 102 | 840 | 412 | 138 | 255 |
originating from the right adrenal gland with a maxi- mum diameter of 5.0cm containing multiple calcifica- tions. A mild contrast capture with no wash-out was noted. Additionally, a PET-CT scan uncovered an inho- mogeneous increased metabolism of the enlarged right adrenal gland, decreasing the likelihood of myelolipoma. No locoregional adenopathy or distant metastases were seen.
After multidisciplinary discussion, a laparoscopic right adrenalectomy was proposed. Surgery was uneventful with removal of the entire lesion (RO resec- tion). Immediately after tumour resection, hydrocorti- sone replacement therapy was initiated to compensate for adrenal insufficiency. Histopathological analysis revealed a right-sided ACC of 48x43 x 57mm with cap- sular invasion and a mitotic rate of 4 per 10 high-power field (pT2MOV1RO, stage II) (Figures 1 and 2). Ki67 index was approximately 30%. Adjuvant treatment with mito- tane was initiated with the intention of lifelong follow-up. Follow-up at two months demonstrated no evidence of recurrence.
Case 2
A 67-year-old woman presented with a right adrenal incidentaloma, coincidentally discovered during the evaluation of an acute cholecystitis with cholestasis. The patient had suffered from alopecia for about five years and complained about increased hair growth around the chin and lower back. She stated that she had lost some weight. Clinical examination revealed features of hirsutism. No other skin abnormalities were observed. Serum cortisol was elevated (22.6 µg/ dL measured at 6 am, reference range: 6.2-18.0 µg/ dL). Aldosterone levels were 152 ng/L (reference range: 17.6-232.0ng/L measured lying down) and renin 11.4ng/L (reference range: 1.6-22.2 ng/L mea- sured lying down). One mg dexamethasone suppres- sion test amounted to 3.7 µg/dL (normal <1.8 µg/dL). DHEAS measured 607.4 ug/dL (reference range:
10.0-256.0 µg/dL) and chromogranin A was 232 µg/L (reference range: 40-170 µg/L). Urinary catechol- amines and urinary cortisol were negative. CT showed a lesion of 9.5x7.1x5.8 cm compressing the vena cava. Acute cholecystitis was also present. Magnetic resonance imaging (MRI) confirmed the presence of a right adrenal mass. The PET scan revealed strongly increased capture in the right adrenal region with central clearing suggestive of necrosis as well as a markedly increased capture at the gallbladder.
Extensive surgery was performed, consisting of a right adrenalectomy, right nephrectomy, and retroperi- toneal lymph node dissection with simultaneous chole- cystectomy. Surgery was uneventful. Perioperatively, a corticoid replacement regimen was given to compen- sate for adrenal insufficiency. Histopathological analysis revealed a low-grade, right-sided ACC with capsular invasion. The right kidney showed no abnormalities. Two reactive lymph nodes were found. The tumour was staged as pT3NOMO with RO resection. Adjuvant treat- ment with mitotane was started and continued for 2years. Secondary adrenal insufficiency occurred after adjuvant treatment. Lifelong substitution therapy with hydrocortisone and 1 alpha-fluorohydrocortisone was required. Follow-up at ten years showed no recurrence.
Case 3
An 84-year-old man was admitted to the emergency department due to an inability to urinate and a decline in general condition following a recent discharge from the geriatric ward. Shortly after previous dismissal, the patient had developed fever. A urinary tract infection had been diagnosed six days earlier by his general practitioner, for which he had been prescribed cipro- floxacin 500mg, 2 times daily. Despite this, fever had remained present, mostly during the day. The patient also mentioned increased dyspnoea for several days. No chest pain was noted. His vital signs showed
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hypertension (171/90mmHg). Clinical examination revealed mild suprapubic tenderness without flank pain. Lung auscultation revealed basal crepitations over the right lung. Urine sediment showed mild hae- maturia without pyuria. Bladder scan showed a resid- ual volume of 400cc in the bladder for which bladder catheterization was performed with evacuation of clear urine. Chest RX showed no infiltrate. Abdominal ultrasound revealed an enlarged spleen adjacent to a heterogeneous structure of dubious clinical signifi- cance. CT exposed a voluminous, inhomogeneous solid mass of 16.0cm in the left hypochondriac region. PET-CT scan uncovered an increased metabolism of the left adrenal gland with central hypocapture corre- sponding to necrosis. Additionally, a small punctate lesion in the right lower lobe of the lung without apparent uptake was detected.
A left adrenalectomy was performed with simulta- neous left nephrectomy, retroperitoneal lymph node dissection, splenectomy, and cholecystectomy. Due to the presence of a significant amount of symptom- atic pleural effusion, a chest tube was placed. Perioperatively, corticosteroid replacement therapy was initiated to compensate for adrenal insufficiency. Histopathological analysis confirmed the diagnosis of ACC. The tumour was adherent to the spleen and kidney. However, there was no progression to these organs. One tumour-free lymph node was found. The greater omentum was tumour-free.
Post-operative period at the intensive care unit was complicated by respiratory insufficiency, iatro- genic right-sided pneumothorax (after drain removal) and atelectasis due to impaction. Despite the addi- tional placement of a second drain for of a persistent air leak, respiratory deterioration continued, with tachypnoea and desaturation with 10 litres of mask oxygenation. Elevated inflammatory parameters were observed, and sputum samples showed infection with Pseudomonas, Enterobacter, Coronavirus, and Herpes Simplex Virus. Pyuria with Pseudomonas was detected as well. Cefepime and a regimen of acyclo- vir were started. However, the patient progressively deteriorated with hypoxia, respiratory and metabolic acidosis, and persistent air leak. He developed acute on chronic renal failure and signs of myocardial isch- aemia with ST depression on ECG and eventually deceased one month after surgery.
Case 4
A 71-year-old man was admitted to our surgery department for the evaluation of a left adrenal inci- dentaloma measuring 10.0cm. The mass was dis- covered on a CT scan for the investigation of abnormal liver function tests. Medical history revealed a traumatic liver rupture at the age of
18 years, an inguinal hernia repair and an appen- dectomy. Clinical examination revealed small spider naevi, but no palpable abdominal masses. Serum cortisol was elevated (16.6 ug/dL measured at 10 am, reference range: 6.2-18.0 µg/dL). One mg dexa- methasone suppression test was 2.2 ug/dL (normal <1.8 ug/dL). DHEAS measured 716 µg/dL (reference range: 34.0-331.0 µg/dL). Urinary catecholamines and several tumour markers (CEA, CA 19.9 and chromogranin A) were normal. And additional PET-CT scan uncovered a large malignant tumour of the left adrenal gland with central necrosis. A left sided ACC was suspected.
After multidisciplinary discussion, debulking of the left hemiabdomen including left adrenalectomy, left nephrectomy, splenectomy, and retroperitoneal lymph node dissection was performed. Histopathological anal- ysis confirmed the diagnosis of ACC with a maximum diameter of 12.0cm. There was no capsular invasion, and the resection margins were tumour-free. The tumour was staged as pT3NOMO. Perioperatively, corticoid replacement therapy was administered to compensate for adrenal insufficiency. As the patient had undergone splenectomy, various vaccinations (pneumococcal, influ- enza B and meningococcal) were prescribed. Adjuvant treatment with mitotane was started and continued for 2years. Due to adrenal insufficiency, lifelong substitution therapy with hydrocortisone was required. Follow-up at ten years with annual imaging showed no evidence of oncological recurrence.
Case 5
A 56-year-old woman presented with a suspected left sided ACC. The patient complained of increased hair growth around the chin, upper lip, and arms and of back pain that did not respond to NSAIDs. She also mentioned a weight loss of 9.0 kg. Medical history revealed a hysterectomy for fibroma uteri. Upon clinical examination, a very large, solid abdom- inal mass was palpable at the level of the left hypo- chondriac region, measuring approximately 20.0cm and reaching below the level of the umbilicus. Blood tests showed a cortisol level of 21.2 µg/dL (measured at 8 am, reference range: 6.2-18.0 µg/dL), ACTH of 34.6 ng/L (reference range: ≤63.0ng/L), testosterone of 102 ng/dL (reference range: 6.0-25.0ng/dl) and renin of 6.7 ng/L (reference range: 1.6-22.2 ng/L mea- sured lying down). Urinary catecholamines and uri- nary cortisol levels were normal. CT of the abdomen and thorax revealed a voluminous, partially calcified, malignant retroperitoneal process in the left hemiab- domen with a diameter of 20.0 cm. There was signif- icant compression of the spleen, left kidney, stomach, pancreas and liver as well as a suspected liver lesion in segment 4a measuring 4.2 cm. CT of the lumbar
spine revealed two bone metastases located at L2-L3. An abdominal MRI confirmed the solitary liver metas- tasis. Both CT and MRI suspected invasion of the renal vein. FDG-PET scan confirmed the lesions seen on CT.
Preoperative antalgic radiotherapy at the level of L2 was given because of osteolytic bone metastases. Debulking of the left upper abdominal quadrant including left adrenalectomy, left nephrectomy, sple- nectomy, retroperitoneal lymph node dissection between the aortocaval and diaphragmatic pillars and liver metastasectomy (segmentectomy II, III and Iva) was performed. Adjuvant mitotane therapy and hydrocortisone were started. One year after surgery, denosumab was initiated because of bone metastases.
Control PET-CT scan three years after surgery showed two small, eccentric foci in liver segments VII and VIII, suspicious for liver metastases, as well as an intense focus on the left C7 pedicle, suspicious for bone metastasis. MRI confirmed the lesion in seg- ment VII of the liver, but a targeted ultrasound could not find a correlate. Repeat MRI after 3months showed a small biliary cyst in segment 7, but no sus- picious solid tissue lesion. Additionally, repeat PET-CT showed no active metabolic hotspots and there was no evidence of recurrence/metastasis. After five years of follow-up, the radiological follow-up was contin- ued (annual imaging). PET-CT 6.5 years after surgery showed a new osteolytic lesion at the site of the right maxilla, presumably due to denosumab-induced osteonecrosis. Denosumab was discontinued; calcium carbonate and vitamin D were prescribed. Repeated imaging showed no evolution of this lesion. Ten years after initial surgery, we could conclude of a favourable evolution with adjuvant mitotane and hydrocortisone treatment.
Discussion
Patient presentation and clinical characteristics
ACC is a rare endocrine malignancy that can occur at any age, with a peak incidence between 40 and 60 years old [3]. Women are more affected than men [3]. Most tumours are sporadic. Nevertheless, one must be cau- tious of the presence of hereditary syndromes such as Lynch syndrome, Li-Fraumeni syndrome, Beckwith- Wiedemann syndrome, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and familial ade- nomatous polyposis coli [3,9].
ACCs may be functionally active. Expression of two or more hormones is frequently seen in ACC [6,10]. Cushing syndrome and/or virilising syndromes are observed in the majority of the patients [1,3]. Hypercortisolism can present as plethora, diabetes mellitus, osteoporosis, purple striae on the abdomi- nal wall, easy bruising, muscle weakness, muscle
atrophy and truncal obesity [6,10]. Frequently, very high cortisol levels in ACC result in glucocorticoid- mediated mineralocorticoid receptor activation [3,11]. As a result, hypokalaemia and hypertension are com- monly observed in patients with hypercortisolism due to ACC [11]. Hyperandrogenism can present with male pattern baldness, virilisation, hirsutism and menstrual abnormalities [10]. Approximately 1-3% of patients have excess oestrogen production, leading to virilisation (increased muscle mass, increased facial hair and amenorrhea) [10]. Secondary amenorrhoea due to a secreting tumour may be misinterpreted by the patient as (early) menopause, leading to delayed presentation and diagnosis [12]. In the presence of vaginal bleeding in the post-menopausal female, an adrenal tumour should be considered if endometrial carcinoma has been excluded [13]. In males, oestro- gen overproduction leads to a syndrome of feminiza- tion, characterized by impotence, diminished libido, testicular atrophy and gynaecomastia [10]. When assessing adrenal masses, androgen or oestrogen production should always lead to the suspicion of malignancy, regardless of the size of the mass [11]. Non-specific symptoms from an abdominal mass, such as abdominal discomfort and nausea, may be present [3]. Constitutional malignancy-associated symptoms such as weight loss, night sweats, fatigue, or fever are rarely present [3]. Asymptomatic and/or non-functioning ACC are increasingly detected on imaging studies intended to evaluate other diseases [5,6]. Non-functional tumours are usually bigger at presentation than functional tumours [10].
Evaluation
Biochemical evaluation includes measuring levels of cortisol, mineralocorticoids, androgens and oestro- gens [3,10]. The diagnosis of hypercortisolism is usually confirmed by a 1 mg dexamethasone sup- pression test, midnight salivary cortisol or elevated 24-hour urine-free cortisol [11]. All patients with suspected ACC should undergo a test for glucocor- ticoid excess, even in the absence of clinical evi- dence of Cushing syndrome [9]. It is essential to prevent postoperative adrenal crisis [9]. ACTH is required to demonstrate ATCH-independency because an adrenal metastasis of an ectopic ACTH-secreting tumour can mimic an ACC [3]. Hypercortisolism due to autonomous cortisol secre- tion in case of an ACC is accompanied by a low ACTH level (<10 pg/mL) [11]. A pheochromocytoma must be ruled out by measuring 24-hour urine or plasma (nor)metanephrine to avoid misdiagnosis and unforeseen intraoperative complications [9].
Abdominal CT is the main imaging modality when evaluating adrenal lesions. Features that should be assessed include tumour size, appearance,
heterogeneity, lipid content, and the rate of washout after intravenous administration of contrast [6]. The suspicion of malignancy increases with tumour size [14]. Adrenal tumours typically appear inhomoge- neous and have irregular borders [9]. ACCs are usu- ally lipid poor and have a high density on unenhanced CT (>10 Hounsfield units) [6]. Functional imaging (positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET)) may be used to confirm the diagnosis of a malignant lesion or to establish the adrenocortical origin of a tumour [11]. ACCs demonstrate a high uptake of 18F-FDG [9]. However, the European Society of Endocrinology reached no consensus for the routine use of 18F-FDG- PET [3]. Patients should in addition undergo an appropriate staging evaluation, including imaging to evaluate for distant metastases, either chest CT and/ or 18F-FDG-PET CT [14]. Preoperative biopsy of sus- pected adrenal neoplasms is not recommended and may even be dangerous in ACCs [3,14].
Differential diagnosis
Due to the poor prognosis of ACC, it is vital to know early if an adrenal mass is malignant or not. The pri- mary differential diagnosis of adrenal lesions includes adrenocortical adenoma, myelolipoma, adrenal metastasis of another tumour, pheochromocytoma, adrenal cyst, ganglioneuroma, sarcoma, and lym- phoma [10]. At the slightest suspicion, the diagnosis of ACC should be excluded. Wariness for ACC must arise if the patient rapidly develops features of adre- nocortical hormone excess or features of a large abdominal mass or if there is evidence of co-secretion of different steroids [15].
Apart from adrenal causes, hormonal excess can be due to a variety of other clinical conditions, such as polycystic ovarian syndrome (PCOS) [10]. PCOS is characterized by androgen excess and leads to a similar clinical presentation, making the distinction between PCOS and adrenal androgen excess an indispensable step in the evaluation [16]. The pres- ence of at least two of three symptoms or findings define PCOS: hyperandrogenism, oligomenorrhea and/or oligo-ovulation, and ultrasonographic poly- cystic ovarian morphology. Most women with hirsut- ism have PCOS [17]. Nonetheless, rapidly developing androgenic manifestations should raise suspicion for ACC rather than PCOS [16].
Pathology
The diagnosis of ACC should be confirmed by histo- pathology based on the resection specimen [3]. ACCs are mostly heterogeneous and may show fibrous bands, in contrast to adrenocortical adenomas that
are well-defined and homogeneous [6]. Areas of hae- morrhage, necrosis, and calcification are often pres- ent in ACC [6]. ACCs tend to invade regional venous structures, adipose tissue surrounding the adrenal gland, and adjacent organs when locally invasive [6]. ACCs are divided based on their characteristic cyto- morphological features: conventional, oncocytic, myxoid, and sarcomatoid [18]. The criteria of Weiss (initially described in 1984 and modified in 1989) are still being used for classification of conventional adrenal cortical neoplasms in adults [6,18]. For a diagnosis of malignancy, at least 3 out of 9 histologic parameters of the Weiss criteria need to be present [18]. In the modified Weiss criteria, there are 5 instead of 9 parameters which makes it easier to apply [6,18].
The WHO classification includes additional multi- parameter diagnostic algorithms to support the work-up of adrenal cortex neoplasms: the reticulin algorithm, the Lin-Weiss-Bisceglia system, and the Helsinki score [18]. First, the reticulin algorithm can be used for conventional, oncocytic and myxoid adrenal cortical tumours [18]. This algorithm consists of a 2-step process: the histochemical analysis of the reticulin framework followed by detection of 3 malignancy-related Weiss criteria (necrosis, high mitotic rate, and venous invasion) [19]. Secondly, the Lin-Weiss-Bisceglia system was developed to evaluate oncocytic adrenal cortical carcinomas [18]. The algo- rithm consists of major (high mitotic activity, atypical mitosis, or venous invasion) and minor criteria (large size, necrosis, capsular invasion, or sinusoidal inva- sion) [20]. The presence of one major criterion indi- cates malignancy [20]. When at least one minor criterion is present, the tumour should be considered ‘borderline’ because of the uncertain malignant potential [20]. Lastly, the Helsinki score can be used for conventional, oncocytic, and myxoid adrenal cor- tical neoplasms [18]. The score uses 3 criteria (mitotic index, necrosis, and proliferation index) to predict metastases in adrenocortical tumours [21].
Extensive morphological evaluation is essential in the work-up of adrenal neoplasms. Nonetheless, cer- tain immunohistochemical biomarkers provide added value. The use of steroidogenic factor 1 (SF1) immu- nohistochemistry is encouraged. It has been shown to be the most reliable and specific biomarker of adrenal cortical origin [22]. Furthermore, SF1 can be used as a prognostic marker because a high expres- sion level correlates with a poor prognosis [23]. Other biomarkers of the adrenal cortex such as Melan-A, alpha-inhibin, and calretinin may also be used [24]. Ki67 immunohistochemistry is recom- mended for the prognostic stratification of ACC [3]. Higher Ki67 values are correlated with poorer prog- nosis [3]. Depending on the differential diagnosis, other immunohistochemistry markers may be con- sidered [3].
Staging
The 8th edition of the tumour, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) was recently revised [25]. T1 consists of a tumour smaller than or equal to 50mm in greatest dimension with no extra-adrenal invasion [25]. T2 includes tumours with a size of over 50 mm without local invasion [25]. Tumours in T3 cat- egory are ACC with local invasion, but do not invade adjacent organs [25]. T4 is characterised by more extensive invasion, either infiltration of the tumour in adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) or a tumour thrombus in the vena cava and/ or renal vein [25]. The TNM staging determines the stage of the tumour [25]. A contralateral adrenal tumour can be found in approximately 5% of the patients [11].
Therapy
The median overall survival of all ACC patients is about 3-4 years [3]. Complete surgical removal of the tumour is the main and only potentially curative treatment option in ACC. Surgery consists of an adre- nalectomy, aiming for a microscopically margin-free (R0) resection. It is mandatory to perform a complete ‘en-bloc’ resection of the tumour, including the peri- adrenal adipose tissue and, if needed, adjacent organs [14,26]. Intraoperative tumour capsule rupture or spillage must be avoided at all cost [14]. If the first surgery was suboptimal with macroscopically incomplete (R2) resection, repeat surgery should always be discussed in a multidisciplinary team [3]. Open surgery is the standard surgical approach for confirmed or highly suspected ACC due to its ability to create an adequate visual exposure of the tumour mass [3,14,27]. A laparoscopic approach is reasonable in a selected group of patients with localized tumours <6cm, under the provision that the surgeon has suf- ficient experience in this type of surgery and there is no local invasion [2,3,14]. If a laparoscopic approach is selected, the transperitoneal approach in the flank position is preferred, but there is no evidence of the superiority of this approach in the literature [14]. A recent meta-analysis shows comparable survival and recurrence-free rates (evaluated at 5 and 10 years) between open and laparoscopic surgery [27]. A tem- porary cortisol deficiency in patients with cortisol-secreting ACC is often observed after radical resection, requiring a glucocorticoid (preferably hydrocortisone) replacement postoperatively [1,3]. Perioperative glucocorticoid replacement is therefore recommended in all patients with hypercortisolism that undergo surgery for ACC [3]. The dose of gluco- corticoid should be tapered on an individualized basis [3].
Adjuvant therapy
Mitotane, an orally administered adrenolytic drug, inhibits adrenal steroid production, and has a cyto- toxic effect on adrenal tissue. A meta-analysis reported a decreased recurrence rate and mortality with adjuvant mitotane after resection of ACC [28]. The European Society of Endocrinology suggests adjuvant mitotane treatment in those patients with- out macroscopic residual tumour after surgery, but with a high risk of recurrence [3]. However, adjuvant therapy options should be discussed for each patient. Determinants that result in a higher risk of recur- rence are stage III tumours, R1-Rx resection, or Ki67> 10% [3,26]. Ki67 is a nuclear antigen that is a marker of active cell proliferation. The optimal dura- tion of mitotane treatment is unknown, but a treat- ment for at least 2years is suggested [3]. From a treatment duration of five years, the rate of recur- rence is potentially too low and the treatment-related toxicity too high to advise continuation of mitotane treatment [3]. Mitotane leads to functional adrenal cortex insufficiency. Along with mitotane, adjuvant treatment with hydrocortisone should be initiated on the first day of treatment [26].
There is no consensus on adjuvant radiation ther- apy after initial surgical resection [3,10]. A recent meta-analysis showed that adjuvant radiation after resection provides a significant improvement in over- all survival compared to resection only [29]. A limita- tion of the study is the heterogeneity of the included studies. The combination of radiotherapy and mito- tane is biologically beneficial but is associated with higher toxicity [26]. More research regarding the effi- cacy of adjuvant radiotherapy is needed.
Surveillance
Follow-up should be conducted every 3 months for the first 2 years [11,14,30]. Depending on the risk of recurrence, follow-up will thereafter be performed every 4 or 6months [14]. After 5 years, follow-up should be implemented every 6-12 months for at least 10 years [9,14,30]. During follow-up, radiological imaging every 3months for 2years and then every 3-6 months for a further 3 years is recommended [3]. After these five years, the radiological follow-up is often continued (annual imaging) because there are limited studies investigating this issue [3].
Advanced ACC
Metastatic ACC is an aggressive disease with few treatment options [31]. In case of advanced dis- ease, resection of metastatic ACC is rarely curative, but may be associated with prolonged survival [14]. The use of other local therapeutic modalities
(e.g. radiotherapy, radiofrequency ablation, cryoab- lation, microwave ablation, or chemoembolization) in addition to surgery to achieve RO resection should be discussed in a multidisciplinary team on an individual basis [3,14]. Surgical therapy is rec- ommended for patients presenting with limited intra-abdominal metastases at the time of initial diagnosis, provided that complete resection of all lesions appears feasible [3]. Metastasectomy pro- longs patient survival and has a prognostic value [2,31]. In case of limited extra-abdominal lesions, therapy aimed at long-term tumour control of these lesions in addition to adrenal tumour resec- tion is preferred [3]. In both cases, mitotane treat- ment should be started as soon as clinically possible [3]. If the patient is not eligible for local treatment at the time of diagnosis, mitotane monotherapy or combination of etoposide, doxo- rubicin, and cisplatin (EDP) in combination with mitotane is recommended by the European Society of Endocrinology [3]. However, it remains import- ant to assess the risk-benefit ratio for each patient [3].
Conclusion
Adrenal masses are being detected at increasing rates due to the widespread use of imaging. It is important to elaborate on such incidentalomas as the prognosis may be dire. Adrenal cortical carci- noma is a rare and aggressive tumour (0.5-2 cases per million per year). Suspicion of ACC might arise if the patient rapidly develops features of adrenocorti- cal hormone excess, features of sex hormone excess, or symptoms of a large abdominal mass. However, some patients will only manifest symptoms when the disease has advanced. Early evaluation and manage- ment are crucial for this aggressive entity. A multidis- ciplinary and individualised approach is important due to the rarity of the disease. Surgery can be per- formed with curative intent. Adjuvant mitotane may be considered for patients with a high risk of recurrence.
Authors contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by author 1. The first draft of the manu- script was written by author 1, and all authors commented on previous versions of the manuscript, which was edited accordingly. Images were provided by author 3. All authors read and approved the final manuscript.
Informed consent
The patients provided written informed consent.
Disclosure statement
All authors have no conflicts of interest. The results pre- sented in this paper have not been published previously in whole or part. There are no prior publications or submis- sions with any overlapping information.
ORCID
Liesbeth Verlinde iD http://orcid.org/0009-0001-1793-4163 Sam Kinet iD http://orcid.org/0000-0001-7220-3489 Klaas Van Den Heede iD http://orcid.org/0000-0003-3642- 9514
Nele Brusselaers iD http://orcid.org/0000-0003-0137-447X Sam Van Slycke iD http://orcid.org/0000-0002-8292-9475
Data availability statement
The data underlying this article will be shared on reason- able request to the corresponding author.
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