OXFORD
Young BJS
Adrenocortical carcinoma: what you at least should know
Charles de Ponthaud1,2 (D, Malanie Roy2,3 and Sébastien Gaujoux1,2,*
1Department of Digestive and Endocrine surgery, AP-HP Pitié-Salpêtrière Hospital, Paris, France
2Sorbonne University, Paris, France
3Department of Endocrinology, AP-HP Pitié-Salpêtrière Hospital, Paris, France
*Correspondence to: Sébastien Gaujoux, Department of Digestive and Endocrine Surgery, AP-HP Pitié-Salpêtrière Hospital, Sorbonne University, 47-83 Avenue de l’Hôpital, 75013 Paris, France (e-mail: sebastien.gaujoux@aphp.fr)
Adrenocortical carcinoma (ACC) is rare, with an incidence of 0.5-2 per million per year. ACC usually occurs in the fifth or sixth decade1 with a slight female predominance (sex ratio 1.5 : 1). Most cases are sporadic, but ACC has also been associated with some hereditary syndromes including multiple endocrine neoplasia type 1, Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous polyposis, and Beckwith-Wiedemann syndrome. The prognosis of ACC is heterogeneous, with median overall survival of 3 years. Surgery remains the only hope for cure2. Diagnosis may be challenging especially when faced with an adrenal incidentaloma. Its management requires a multidisciplinary approach that includes at least surgeons, endocrinologists, pathologists, nuclear medicine physicians, and radiologists. Here, the authors present what surgeons should at least know to provide the highest standard of care to patients with ACC, as summarized in Fig. 1.
When to suspect and how to diagnose adrenocortical carcinoma
Clinical presentation
ACC is most often symptomatic at presentation. Symptoms are frequently related to hormone oversecretion, mainly hypercortisolism (Cushing’s syndrome), but this also includes androgen excess (virilization in women), oestrogen excess (feminization in men), or, less frequently, mineralocorticoid oversecretion. With a median ACC size of around 10 cm, symptoms may also be related to the tumour mass leading to non-specific abdominal pain, nausea/vomiting, digestive distension, and/or inferior vena cava syndrome caused by tumour thrombus with extension that can reach up to the right atrium.
Conversely, in 10-20% of cases, ACC is diagnosed as an incidentaloma. The prevalence of incidentalomas is increasing constantly owing to the widespread use of cross-sectional imaging3. Although adrenal incidentalomas are frequent, ACC accounts for only 1-4%4 of them, and presents significant diagnostic challenges because of its overlap with other adrenal tumours (for example atypical adenoma, neurogenic tumours).
Biological assessment
About half of ACCs secrete hormones, and a biological work-up is required to identify them and exclude phaeochromocytoma.
When ACC is suspected, the following tests, as for incidentaloma, are required4:
· Measurement of fasting blood glucose and potassium levels.
· Measurement of cortisol levels at midnight in plasma and/or over 24 hours in urine, a 1-mg overnight dexamethasone suppression test, and basal plasma level of adrenocorticotrophic hormone to assess autonomous glucocorticoid secretion. In ACC with hypercortisolism, postoperative hydrocortisone treatment should never be forgotten to prevent postoperative adrenal insufficiency.
· Measurement of plasma-free catecholamines or urinary fractionated catecholamines to exclude phaeochromocytoma.
This initial work-up should be completed with more specific and targeted tests:
· Evaluation of sex steroid secretion, including serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione, 17- hydroxyprogesterone, compound-S, 11-deoxycorticosterone, testosterone in women, and 17ß-oestradiol in men and postmenopausal women. Recently, a urine steroid metabolomics approach using steroid profiling appeared to discriminate benign from malignant adrenocortical tumours when associated with CT features5. Although rare, this secretion, combined with hypercortisolism, marks the diagnosis of ACC in the event of an adrenal incidentaloma3.
· Assessment for hyperaldosteronism, including measurement of serum aldosterone and renin only in patients with arterial hypertension and/or hypokalaemia.
Imaging
CT is the cornerstone of the investigation of adrenal lesions. Malignant tumour can be suspected and distinguished from benign lesions if it fulfils the following criteria: unilateral lesion larger than 4 cm, unenhanced density greater than 20 Hounsfield units (HU) (better specificity than previous 10-HU cut-off), heterogeneous (with or without necrosis or calcifications). Contrast enhancement is not a determining factor in adrenal incidentaloma, unlike tumour perfusion kinetics, which improve diagnostic accuracy. Thus, malignant adrenal lesions demonstrate
Clinical presentation
Biological assessment
Symptomatic Hormone oversecretion Mass syndrome Vena cava thrombus
Hypercortisolism
Cortisol level (plasma) at midnight Cortisol level (urine) 24 h
Metanephrines Plasma-free
or
Dexamethasone suppression test Basal ACTH plasma level
urinary fractionated
Phaeochromocytoma?
H
versus
Hyperaldosteronism Potassium level Aldosterone + renin (plasma)
H
Biopsy
Sex steroid secretion
lncidentaloma
DHEA-S, 11-DOC,17ß-oestradiol,17-OH-P, Compound-S, androstenedione, testosterone
DIAGNOSIS
Imaging work-up
1 Local diagnosis: abdominal CT without and with contrast enhancement
Malignant
Benign
> 4 cm
< 4 cm
20 HU
< 20 HU
Heterogeneous
± calcifications
Heterogeneous
+ necrosis
APW < 60%
APW > 60% RPW>40%
RPW < 40%
2 Extent assessment Locoregional: MRI Distant metastasis: Thoracic CT + [18F]FDG PET
Gold standard: surgery
Adjuvant treatment Depends on risk of recurrence
v High-volume expert centers (>15-20/year)
V Low risk ENSAT 1-2 and Ki 67 ≤ 10% and R0
Intermediate and high risk
V En bloc ± multiorgan resection
TREATMENT
CI
CI
V OPEN > Laparoscopy
Mitotane
v Lymphadenectomy (> 5 nodes) periadrenal and renal hilar
Follow-up
CI
CI
+ coeliac axis
± para-aortic
± pericaval
Follow-up Long term (> 10 years)
Combining clinical examination + biology CT + [18F]FDG PET
Aim: R0 resection + no capsular rupture
Fig. 1 What surgeons should at least know to provide the highest standard of care to patients with adrenocortical carcinoma
ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate; 11-DOC, 11-deoxycorticosterone; 17-OH-P, 17-hydroxyprogesterone; HU, Hounsfield units; APW, absolute percentage washout; RPW, relative percentage washout; FDG, fluorodeoxyglucose; ENSAT, European Network for the Study of Adrenal Tumors.
a slower washout of contrast at 10-15 min of acquisition, with an absolute percentage washout (APW= 100x [HU1min - HU15min]/ [HU1min - HUnative]) of less than 60%, and a relative percentage washout (RPW= 100x [HU1min - HU15min]/HU1min) of below 40%, where HU1min and HU15min are the HU measured at 1min (portal venous phase) and 15 min (delayed phase) after contrast administration, and HUnative is the HU measured on non- enhanced scan. MRI with unenhanced T1, T2 and fat- suppression sequences can help to further characterize the lesion when CT criteria are not met definitively. Diffusion- weighted sequences appear to have limited additional value in adrenal tumours. Imaging should also assess locoregional extension, and especially venous (renal or vena caval) extension, lymph node involvement, or distant metastases.
Although functional imaging plays a key role in the diagnosis of most endocrine tumours, its usefulness seems more limited in ACC. Most specific functional imaging techniques, such as scintigraphy with [131I]noriodocholesterol, or [11C]metomidate PET-CT are unable to distinguish an ACC from a benign tumour. [18F]fluorodeoxyglucose (FDG) PET can, however, provide a diagnostic complement for tumour characterization, with an adrenal-to-liver standardized uptake value (SUV) ratio cut-off greater than 1.5 in favour of ACC diagnosis (versus atypical adenoma) and a positive correlation uptake with Ki-67 expression. Additionally, [18F]FDG PET helps to better assess locoregional and metastatic extension. Percutaneous biopsy is not recommended for a resectable ACC. Its diagnostic performance is quite poor (sensitivity 70%, specificity 98%), with a significant risk of tumour spread.
Which surgery for adrenocortical carcinoma?
The indication for surgery should always be discussed by a multidisciplinary team6 . When R0 resection is achievable, the standard procedure is en bloc resection of the suspected ACC by laparotomy with associated lymphadenectomy, performed in a tertiary centre by an experienced surgeon in adrenal and oncological surgery (over 15-20 procedures per year)1,4,7. Lymphadenectomy appears to be of oncological benefit8. It should include at least periadrenal and renal hilar nodes1 with a minimum of five nodes. A more extensive lymphadenectomy (coeliac axis, para-aortic, paracaval nodes) can be suggested, despite low-quality evidence. In practice, however, it neither standardized nor systematically performed, mainly owing to a lack of knowledge of the anatomical lymphatic drainage of the adrenal glands9.
A laparoscopic transperitoneal approach may be an option for tumours smaller than 6 cm without signs of local invasion10. Capsular rupture, spillage, and non-R0 resection should be avoided. Therefore, the operation must be performed by a surgeon experienced in adrenal, oncological, and laparoscopic surgery.
For lesions invading adjacent organs, en bloc surgery may include resection of neighbouring organs, most frequently kidney, spleen, pancreas, liver, stomach or colon, to ensure R0 margins and/or prevent tumour rupture. Systematic ipsilateral nephrectomy has not shown oncological benefit, may impair renal function, and cannot be recommended11. In patients with vena cava tumour thrombus, which is observed particularly in right ACC, the upper level of caval extension (relationships with hepatic vein confluence and right atrial extension) should be documented accurately. Direct invasion into the venous wall is often limited
and can be treated by partial wedge resection and direct closure, or with interposition of a patch. Caval thrombectomy can usually be performed by cross-clamping the inferior vena cava, but hepatic vascular exclusion, intrapericardial hepatic vascular exclusion or cardiopulmonary bypass with hypothermic circulatory arrest might be necessary with prosthetic vena cava replacement on indication.
Currently, there are no robust data on the oncological benefit of neoadjuvant treatment, either for localized or locally advanced ACC12.
In the event of local recurrence, surgery should be considered, ideally in patients with late recurrence (disease-free interval over 12 months) and when the recurrent tumour can be resected radically13. For patients with metastases, surgery is not standard of care, but may be considered in patients with oligometastatic disease that has been stabilized by systemic treatment, and is amenable to R0 resection1,14.
Adjuvant treatment and follow-up
Adjuvant mitotane (OP’DDD) treatment over 2 years is the standard treatment after ACC resection, improving recurrence-free survival15. It is formally indicated for patients at high risk of recurrence (European Network for the Study of Adrenal Tumors (ENSAT) 3-4, or Ki-67 index over 20%, or involved resection margins), and its combination with chemotherapy is currently being evaluated in the ADIUVO-2 study (NCT03583710). In the ADIUVO trial16, patients at low risk of recurrence (ENSAT 1-2, Ki-67 index below 10% and RO resection) had no benefit from mitotane. Adjuvant radiotherapy is not standard of care given its controversial impact on overall survival, but can be discussed in patients with a very high risk of local recurrence, especially after Rx or R1 resection.
Long-term follow-up of at least 10 years is indicated for patients with ACC, and includes a combination of clinical examination, biochemical evaluation, and imaging using CT or MRI. The usual recommended frequency is one assessment every 3 months for the first 2 years, then every 6 months for the next 3 years, and annually for the subsequent 5 years1,17. [18F]FDG PET could be performed if there is any doubt about a recurrence.
Funding
The authors have no funding to declare.
Author contributions
Charles de Ponthaud (Investigation, Methodology, Resources, Software, Writing-original draft, Writing-review & editing), Malanie Roy (Supervision, Validation, Visualization), and Sebastien Gaujoux (Conceptualization, Supervision, Validation, Visualization, Writing-review & editing)
Disclosure
The authors declare no conflict of interest.
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