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The French Journal of Urology
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THE FRENCH JOURNAL Urology
1
AFU
Recommendations
French AFU Cancer Committee Guidelines - Update 2024-2026: Assessment of an adrenal incidentaloma and oncological management
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Pierre-Henri Savoie a,b,*, Thibaut Murez a,c, Laurence Rocher a,d,e, Paul Neuville a,f, Agate Escoffier ª,8, Aude Fléchon a,h, Nicolas Branger ª,i, Philippe Camparo a,], Morgan Rouprêt a,k
a Comité de Cancérologie de l’Association française d’urologie, Groupe organes génitaux externes, Maison de l’Urologie, 11, rue Viète, 75017 Paris, France
b Centre d’urologie UROVAR, Polyclinique les Fleurs, 332, avenue Frédéric-Mistral, 83190 Ollioules, France
” Service d’urologie et de transplantation rénale, CHU de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier, France
Hôpital Antoine-Béclère, service de radiologie, AP-HP, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France
e BIOMAPS, UMR1281, université Paris Saclay, 63, rue Gabriel-Péri, 94270 Le Kremlin-Bicêtre, France
Service d’urologie, hôpital Lyon Sud, hospices civils de Lyon, 165, chemin du Grand-Revoyet, 69310 Pierre-Bénite, France
% Service d’urologie, CHU de Dijon, 14, rue Paul-Gaffarel, 21000 Dijon, France
h Département d’oncologie médicale, Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France
Département d’urologie, Institut Paoli-Calmettes, 232, boulevard de Sainte-Marguerite, 13009 Marseille, France
¿ Institut de pathologie des Hauts de France, 51, rue Jeanne-d’Arc, 80000 Amiens, France
k Sorbonne University, GRC 5 Predictive Onco-Uro, AP-HP, Urology, Pitié-Salpêtrière Hospital, 75013 Paris, France
ARTICLE INFO
Keywords:
Adrenal incidentaloma Adrenocortical carcinoma Malignant pheochromocytoma Adrenal metastasis
ABSTRACT
Introduction: The aim of this publication is to review the initial management procedure for adrenal incidentalomas, and where appropriate, to establish a carcinological management procedure for malignant adrenal tumours. Materials and methods: The multidisciplinary working group updated the CCAFU 2022 recommendations for the carcinological management of adrenal incidentalomas on the basis of a comprehensive PubMed review of the literature.
Results: Although the majority of adrenal masses are benign and nonfunctional, it is important to investigate them because of their serious endocrine potential, and because of certain cancers. Malignant adrenal tumours (MCTs) are essentially adrenocortical carcinomas (ACCs), malignant pheochromocytomas (MPCs), and adrenal metastases (AMs). The work-up for the malignancy of an adrenal incidentaloma includes a full history, physical examination, and a biochemical/hormonal assessment to look for subclinical hormone secretion. Diagnostic hypotheses are sometimes available at this stage, but morphological and functional imaging and histological analysis enable the malignancy assessment to be completed, and a carcinological diagnosis to be made.
Conclusions: SCC and MCC are mostly sporadic, but a hereditary origin is always possible. SCC is suspected preoperatively, but a diagnosis of certainty is histological. The diagnosis of PCM is more delicate and is based on clinical, biological, and imaging findings. The definitive diagnosis of MS requires a percutaneous biopsy. All cases must then be discussed within the COMETE adrenal cancer network.
@ 2024 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
This article provides urologists with recommendations for an initial diagnostic work-up and the subsequent management (discontinuation of follow-up, monitoring or surgery) of unilateral adrenal incidentaloma. Therapeutic management is all the more detailed the more malignant the
work-up suspects it to be. This is based on the recommendations established by the CCAFU in 2022 [1] and on the scientific literature available on PubMed in 2024.
* Corresponding author at: Comité de cancérologie de l’Association française d’urologie, groupe organes génitaux externes, Maison de l’Urologie, 11, rue Viète, 75017 Paris, France.
E-mail address: phsavoie@hotmail.fr (P .- H. Savoie).
Received 5 August 2024; Accepted 16 September 2024
1. General
1.1. Definition
An adrenal incidentaloma (AI) is a supracentimetric adrenal mass detected by chance on radiological examination performed for another reason. Therefore, it is not discovered during neoplastic staging or exploration for hypertension.
These masses can be divided into 3 categories: benign nonfunctional lesions, benign hypersecreting lesions and malignant lesions.
The prevalence varies from 1% to more than 10% in adults, depending on the autopsy or radiology series. A recent publication studied a cohort of 25,356 asymptomatic patients who underwent abdominal CT scans as part of a routine health check: 1.4% had IS [2]. The prevalence increases significantly with age [3-5]. In children, adrenal tumours are very rare and are rarely incidentalomas [6].
In 75% of cases, it is to be a benign nonsecreting adenoma [7]. In the absence of symptoms, it should be monitored or ignored. Malignant adrenal tumours are rare. Therefore, if they are suspected, this justifies multidisciplinary management involving surgeons, endocrinologists, oncologists, nuclear medicine physician and radiologist, if possible, at an expert centre (in France the ENDOCAN-COMETE “Adrenal Cancers” network, accredited by the National Cancer Institute) and internationally (ENSAT in Europe).
Recommendation Table 1
1.2. Epidemiology
The probability of malignancy in AI is low (<5%) [1]. The main histological types and their relative incidences according to several bibliographic sources are presented in Table 1. Malignant adrenal tumours are either primary, affecting the cortex of the gland [adrenocortical carcinoma (ACC) or malignant adrenocortical carcino- ma], or medullary [malignant pheochromocytoma (MPC)], or secondary (mainly bronchopulmonary cancer, and more rarely, melanoma, breast, kidney, ovarian, colon, hepatocellular cancer, etc.). Therefore, adrenal metastases (AMs) rarely involve adrenal incidentalomas (if synchronous, they are discovered during the extension work-up; if metachronous, they are discovered during follow-up). Primary lymphomas, which are exceptional and mostly bilateral, will not be discussed here.
2. Diagnosis
The aim of an aetiological assessment of an AI is to determine whether or not surgery is indicated.
2.1. Clinical assessment
2.1.1. Questioning and clinical examination of an AI The questioning will look for the following:
· a personal history of neoplasia;
Recommendation Table 1
| General | Grade |
|---|---|
| It is advisable to discuss AI cases in the MDT meeting in the event of : - Secreting AI - AI indeterminate: benignity uncertain or growth confirmed (at follow-up) - Surgery envisaged (a minority of AIs justify excision) | Low |
| AI suspected of being malignant or with a known malignancy should be managed in an expert adrenal oncological centre (MDTM) and should be included in therapeutic trials as soon as possible. | Low |
AI: adrenal incidentaloma; MDTM: multidisciplinary team meeting.
| Benign | Nonsecreting adrenal adenoma | 40- |
| 70% | ||
| Secreting adrenocortical adenoma | 20- | |
| 50% | ||
| Cortisol (cortisol-producing adenoma) | 5-8% | |
| - Symptomatic | 1-4% | |
| - Subclinical (MACS) | 20- | |
| 50% | ||
| Aldosterone (Conn's adenoma, with primary aldosteronism) | 2-5% | |
| Pheochromocytoma | 1-5% | |
| Others (cysts, haematomas, myelolipomas, | <10% | |
| ganglioneuromas, etc.) | ||
| Malignant | Adrenocortical carcinoma | 0.4- |
| 4% | ||
| Malignant pheochromocytoma | <1% | |
| Metastasis | 2% | |
| Other (lymphoma, neuroblastoma, sarcoma, etc.) | <1% |
MACS: mild autonomous cortisol secretion.
· familial or associated pathology that indicate a genetic predisposition syndrome for adrenal tumours;
· clinical signs suggestive of underlying neoplasia;
· signs of subclinical hormonal hypersecretion (hypertension (HTN), diabetes, etc.) (Table 2) and possible signs of malignancy (palpable mass, rapid onset of symptoms such as low back pain, occult fever, anorexia, weight loss);
· inquiry into previous imaging.
2.1.2. Clinical examination and questioning according to the type of adrenal tumour
2.1.2.1. Adrenocortical carcinoma. ACCs, which are sometimes asymp- tomatic, are most often discovered during the work-up for hormonal hypersecretion (40-74% of cases) or a tumour syndrome (40-60% of cases). Less frequently (10-20% of cases), it is in the context of the AI. Rarely, it is a paraneoplastic syndrome (fever, deterioration of the general health status, hypoglycaemia) that guides the diagnosis.
Hypersecretion may involve the following:
· cortisol should be investigated for Cushing’s syndrome (~ 30%);
· androgens with symptoms of virilisation (acne, hirsutism or other signs of virilisation) in women (~ 20%). One third of virilizing tumours are malignant;
| Symptoms and clinical signs | Adrenal medulla | Adrenal cortex |
|---|---|---|
| Diabetes | PC | |
| HTN | PC | ACC |
| HTN with primary hyperaldosteronism | 1% of ACC | |
| Pallor or peripheral vasoconstriction | PC | |
| Symptomatic "Menard" triad, complete or not | PC (+ + +) | |
| Heart failure (dilated cardiomyopathy) | PC | |
| Severe constipation | PC | |
| Change in general health status, fever | MPC | ACC |
| Lumbar contact or palpated abdominal mass | MPC | |
| Cushing's syndrome | ACC | |
| Hyperandrogenism in women | ACC | |
| Signs of feminisation in men | ACC | |
| Osteolytic bone events | MPC | ACC |
| (osteolysis) |
HTN: hypertension. Key: Menard triad: pulsatile headaches, heart palpitations and tachycardia and profuse sweating; Cushing’s syndrome (weight gain, facial plethora, Cushingoid facies, obesity, HTN, purple striae atrophicae, easy bruising).
· oestrogens with signs of feminisation (gynaecomastia) in men (~10%). Feminizing tumours are almost always malignant [8,9];
· mixed secretion (~ 35%).
ACCs are almost always sporadic, although certain congenital and/or hereditary diseases may exceptionally be associated with them (NME type 1, Lynch syndrome, Li-Fraumeni syndrome, Gardner syndrome) [10]. These factors should be systematically investigated.
2.1.2.2. Pheochromocytoma (PC) and malignant PC (MPC). PC is a chromaffin tumour that develops in the adrenal medulla. There is no histological criterion to formally differentiate MPCs from PCs. Only the presence of metastasis in nonchromaffin tissue in the initial or follow-up assessment confirms malignancy [11]. This means that all PCs must be monitored for life.
Only 20% of PCs are asymptomatic [12]. The clinical picture for PC (due to an excess of catecholamines) may include: HTN with hypokalaemia, orthostatic hypotension, altered general health, consti- pation and pallor due to peripheral vasoconstriction (symptoms secondary to catecholaminergic hypersecretion). The typical symptom triad known as the “Menard triad” (pulsatile headaches, heart palpitations and tachycardia and profuse sweating) is inconsistent.
The most common metastatic sites for PCM are bone, followed by the lungs, lymph nodes, and liver [11,13].
Exceptionally, the symptomatology related to MPC metastases (bone pain, fever, altered general health, etc.) is what leads to the discovery of the disease. The persistence of clinical signs after adrenalectomy for PC is suggestive of residual metastases and therefore of MPC [1].
Ten percent of MPCs may occur in the context of genetic diseases such as multiple endocrine neoplasia syndrome [1,14], von Hippel-Lindau disease, mutation of succinate dehydrogenase subunit B (SDHB), neurofibromatosis type 1, Sturge-Weber syndrome, and tuberous sclerosis [1]. Therefore, in case of MPC, a hereditary context should be routinely ruled out.
A systematic oncogenetic consultation is recommended. Approxi- mately twenty genes predisposing patient to pheochromocytomas/ paragangliomas have been reported in the literature and, of these, the genes most frequently carrying a constitutional mutation are SDHB, SDHD, VHL, RET and NF1 [11,15].
2.1.2.3. Adrenal metastasis. In most instances, AM is asymptomatic. Metastases do not usually cause adrenal insufficiency as loss of endocrine function would require the destruction of at least 90% of the glandular tissue.
2.2. Paraclinical check-up
Before the imaging criteria are reevaluated, a minimum biological work-up should be carried out.
2.2.1. Biochemical evaluation
In addition to fasting blood sugar and potassium levels, hormone measurements are recommended as first-line tests.
The serum cortisol level, sometimes normal, is not sufficient to detect excess cortisol secretion. A more precise screening test is recommended using a dexamethasone suppression test, involving the injection of 1 milligram of dexamethasone at 11 pm to reveal a secreting tumour with normal cortisolaemia (mild autonomous cortisol secretion or MACS) [3].
Recommendation Table 2 [3]
2.2.2. Second-line biological tests
A genetic assessment is only performed if there is an indication of a hereditary context, particularly in case of phaeochromocytoma. A complementary hormonal assessment may be considered in an endo- crinological setting.
Recommendation Table 2
[3].
| First-line hormonal assessment of an AS | Secretion |
|---|---|
| - Fasting blood glucose | Catecholamines |
| - Cortisol level at 8 am - Dexamethasone braking test (1 mg at 11pm) | Glucocorticoids |
| - Kalaemia | Mineralocorticoids |
| - Fractionated urinary metanephrines (24-hour urine) along with urine creatinine UNLESS the diagnosis of adenoma is | Catecholamines |
| certain on imaging (CTscan or MRI) | |
| - Plasma free metanephrines IF renal failure | |
| Second-line hormonal assessment of an AS | Secretion |
| If 8 h cortisol level increased (>138 nM or 5 microg/mL): - Cortisol levels (plasma or saliva) at midnight or | Glucocorticoids |
| - Free urinary cortisol on 24h urine or - Plasma ACTH in the morning. | |
| If hypertension and/or hypokalaemia: Angiotensin/Renin ratio | Mineralocorticoids |
| If clinical signs or suspected ACC : | Sex steroids |
| - Serum DHEA sulphate | |
| - 17- OH Progesterone - Serum testosterone - Compound S | |
In patients with AI and hypertension and/or hypokalaemia, primary hyperaldosteronism should be investigated with an angiotensin/renin ratio [7].
When clinical signs of virilisation are described, serum tests for excess androgens should be performed [7].
2.2.3. Radiological evaluation
The imaging criteria favoring a benign tumor are summarized in Table 3.
2.2.3.1. Scanner. The characteristics of the scan performed (regions, phases before and after injection) depend on the biochemical work-up and therefore on the diagnostic orientation. This data should be available to the radiologist. The important criteria for the characterizing an AI are follows.
2.2.3.1.1. Tumour size. An IS > 4 cm in size is no longer an exclusive criterion for excision, but the size of an IS can be predictive of its malignancy, regardless of the imaging modality used. Above 6 cm, the proportion of malignant tumours is 25%, whereas it is less than 2% for masses of less than 4cm [16]. For adrenocortical carcinomas, the specificity of the malignancy diagnosis is 52%, 80%, 95% and 98% respectively for diameters > 4 cm, > 6 cm, > 8 cm or > 10 cm, respective- ly [1].
For PCs, the specificity of the malignancy diagnosis is 20%, 65% and 89% for diameters of 4 cm, 6 cm and 8 cm [17].
2.2.3.1.2. Other CT characteristics. Heterogeneity on films (injected or not) is inconsistent with a simple nonsecreting adenoma. This classifies
| Imaging | Criteria |
|---|---|
| Spontaneous contrast enhancement CTscan | HU <10 |
| MRI | Loss of intensity on out-phase sequences with a fat-rich adenoma |
| Contrast-enhanced CTscan with | Absolute washout >60% |
| delayed phases | Relative washout > 40% |
| 18FDG PET scan | No hypermetabolism or inferior metabolism in the liver |
CT: computer tomography; CT: CTomography; MRI: magnetic resonance imaging; PET: positron emission tomography.
the AI as indeterminate and justifies further investigations. This is a pejorative criterion until it is proven otherwise. An AI > 4 cm and that is heterogeneous must be operated on [3].
Spontaneous density is one of the most robust aetiological criteria, although its variability for the same type of tumour should be known. Indeed, many current scanners using spectral imaging, with reconstruc- tions of a series in virtual spontaneous density, may have variations in spontaneous density for the same lesion in the same patient [18,19]. Spectral imaging is used to differentiate adenomas, which are rich in fat, from malignant lesions, which are poorer in fat [1,16]. Below the threshold of 10 HU, benignity is almost certain, with a specificity of approximately 98% [20]. In a retrospective review of 216 patients who had undergone adrenalectomy, all patients with benign features on a CT scan had a benign pathology [21]. Thus, a homogeneous IS on CT with a density <10HU is certainly benign. However, with this approach, approximately 30% of lipid-poor adenomas have a density greater than 10 HU. Thus, an injection with so-called early acquisition (despite a portal time of 60 s), followed by late acquisition (between 10 and 15 minutes), makes it possible to catch up with certain adenoma diagnoses [22].
The washout rate is thereby calculated. It reflects the rate of release of the contrast medium from the tumour after enhancement. Hypervascular tumours with a high absolute washout > 60% and/or a relative washout >40%, suggestive of an adenoma, are diagnosed as benign [7]. This approach is not specific because certain hypervascular malignant tumours such as ACC, pheochromocytoma or certain metastases (kidney, melanoma) have such characteristics.
Recommendation Table 3
2.2.3.2. Second-line tests.
2.2.3.2.1. Magnetic resonance imaging (MRI). Compared with CT, abdominal MRI does not provide any additional diagnostic information (its sensitivity and specificity are slightly lower than those of CT, which are 78% and 87%, respectively, for tissue characterisation) [3,16]. An additional MRI is not necessary if the diagnosis has already been established by CT. An unambiguous result in favour of an adenoma for an IS discovered on MRI (fall in the T1 signal in phase and phase opposition) does not require an additional CT scan.
MRI provides a better assessment of the local and venous invasion of a potentially malignant tumour because of its better contrast resolution [7]. On the other hand, it is a suitable monitoring tool for young patients to limit the need for repeated irradiation.
2.2.3.2.2. Nuclear imaging. 18F-FDG positron emission tomography (PET). When faced with an 18F-FDG hypermetabolic adrenal lesion, four main malignant diagnoses are considered: PCM, CCS, MS, or lymphoma. Benign hypermetabolic lesions are PCs, secretory adenomas, or inflammatory pathologies (sarcoidosis, granulomatosis).
An SUV max tumour/SUV max liver ratio ≥ 1.45 is strongly predictive of malignancy [23].
Recommendation Table 3
| First-line assessment | Grade |
|---|---|
| The first-line tests for an AI should detect signs of malignancy and hypersecretion of adrenal hormones. | Low |
| - The secretory work-up is based on the history, the clinic (Cushing's syndrome) and systematic biological tests (8-hour cortisol level, | |
| dexamethasone suppression test, kalaemia, metanephrines unless adenoma | |
| is certain). | |
| - The malignancy assessment is based on the patient's history, clinical findings and imaging, and may sometimes include the detection of suspicious biological elements (sex steroid assays in cases of suspected ACC). | |
| AI should be scanned without injection to determine their homogeneity and HU density. | High |
AI: adrenal incidentaloma; HU: Hounsfield units.
In cases of suspected SCC, 18FDG PET is the scintigraphic examination of reference, both in the diagnostic phase and for follow-up [24,25].
In practice, 18FDG PET is authorised in France for the treatment of IS, and is considered in cases of suspected malignancy [10,26].
Positron emission tomography using 18F-DOPA (Fluoro-18-L-Dihydrox- yphenylalanine) at the somatostatin receptor (68 Ga-DOTATOC). If PC is suspected, the tracer of choice is 18F-DOPA as this is the most sensitive. It is useful for a positive diagnoses and for highlighting any secondary localisations, with a sensitivity close to 100%.
It can be combined with 18FDG [27].
DOTATOC is the most sensitive examination in the staging of paraganglioma [27] and therefore in cases of suspected MPC It is used to assess the eligibility of patients suspected of having metastatic PCM for metabolic radiotherapy vectored by177 Lu-DOTATATE.
Scintigraphy using Meta-iodo-benzylguanidine labelled with iodine 123 (123-I-MIBG). Although less commonly used at the diagnostic stage, it uses a tracer specific to the adrenal medulla. It is still used in PCs when 18F-F-DOPA PET is unavailable.
It is also essential for checking the eligibility of patients suspected of having metastatic CMP for metabolic radiotherapy [28].
Recommendation Table 4
2.2.3.2.3. The role of percutaneous biopsy. A percutaneous biopsy is rarely useful. It is limited to the suspicion of AM, in the event of a history of neoplasia [1,29].
Lesions > 10 HU are malignant in 70% of patients with a history of extra-adrenal malignancy. If the characterisation of these lesions changes their clinical management, adrenal biopsy (and 18FDG PET) may be considered [7]. Three criteria are essential [3]:
· the lesion is nonsecreting (in particular, a pheochromocytoma has been ruled out);
· the lesion was not characterised as benign by imaging;
· management must be modified by histology knowledge. Biopsy is contraindicated:
· in the case of PC, the risk of malignant hypertension due to catecholamine discharge must be formally ruled out [3]. In exceptional cases, it may be necessary to confirm the diagnosis of an adrenal lesion that has metastasised and is irresectable (in which case it must be
Recommendation Table 4
| Second-line imaging for AI | Grade |
|---|---|
| An abdominal MRI does not provide any additional diagnostic information compared with CT scans, so additional MRI is not necessary if the diagnosis has already been established by CT scan. | Low |
| An unambiguous result in favour of an adenoma for an IS discovered on MRI does not require an additional CT scan. | Low |
| For AI, MRI is a second-line examination: - In the event of contraindication to CT injection - In the case of an AI suspected of being malignant (to determine local invasion) - For monitoring (to avoid iterative irradiation) | Low |
| 18F-FDG PET scans are routinely recommended in cases of suspected ACC and SI suspected of malignancy or associated with a history of extra-adrenal cancer. | High |
| For the MPC, the following may be carried out - 68Ga-DOTATOC in a sporadic or SDH mutation context. It will be used to select candidates for metabolic radiotherapy vectored by 177Lu- DOTATATE - 18F-DOPA in a context of RET, VHL, MAX, EPAS1 mutation | High |
| If there is a history of extra-adrenal cancer, AI is a metastasis until proven otherwise. A biopsy should be suggested after ruling out ACC or PC. | High |
AI: adrenal incidentaloma; MRI: magnetic resonance imaging; CT: computer tomography; MPC: malignant pheochromocytoma.
combined with anti-SF1 immunohistochemical staining), except in cases of suspected MPC;
· in cases of suspected ACC [3,24] there is a risk of tumour dissemination due to capsular rupture [1].
3. Therapeutic management
Treatment recommendations are preoposed in the form of decision algorithms on the basis of the CCAFU 2022 guidelines, which were updated in 2024 from Pubmed. The first algorithm proposes the management of an AI on the basis of the results of the initial work-up (Fig. 1). Specific algorithms are proposed for suspected ACCs (Fig. 2) and suspected MPCs (Fig. 3).
3.1. Adrenal incidentaloma of undetermined nature
3.1.1. Surgery
3.1.1.1. Indications. An asymptomatic, nonfunctioning unilateral adrenal mass evident benign features on imaging should not be operated on.
In all other cases, an individual approach is recommended [30].
3.1.1.1.1. Size. ACCs are often > 4 cm, but some small ACCs (less than 4 cm) can be detected [10].
AS < 4 cm:
· a homogeneous mass with a spontaneous density HU ≤ 10 can be considered benign. In this situation, no further work-up or follow-up imaging is recommended [3];
· a homogeneous mass with a spontaneous density of between HU 11-20, and a normal hormonal work-up: in this case additional imaging is recommended (CT scan with washout calculation, MRI coupled with spectroscopy, 18FDG PET) [3]. Another option is to repeat a non- injected CT scan or MRI within 12 months [7];
· a heterogeneous mass mean that the case should be given to a referral MultiDisciplinary Team Meeting (MDTM) at an expert centre for
further imaging, or immediate surgery is recommended. In the absence of surgery, monitoring at 6-12 months by non-injected CT scan or MRI is recommended [3].
AS ≥ 4 cm: an ACC must be ruled out:
· a homogeneous mass with a spontaneous density HU ≤ 10 can be considered benign. In this situation, no further work-up or follow-up imaging is recommended [3]. If the tumour is larger than 6 cm, the CCAFU recommends that this decision be validated by a specialist MDTM, as the majority of adrenocortical carcinomas are ≥ 4 cm and even > 6 cm in size at diagnosis [24,31];
· for a homogeneous mass with a spontaneous density of HU 11-20, and a normal hormonal work-up: it is recommended that the patient be referred to a referral RCP in an expert centre for further imaging or surgery from the outset. In this situation, follow-up imaging at 6- 12 months (spontaneous contrast CT or MRI) is recommended. If progression is less than 3 mm, follow-up should be discontinued. In the event of progression > 20% or > 5 mm, surgery is indicated from the outset;
· for a homogeneous mass with a spontaneous density of HU > 20, the risk of malignancy is high, requiring referral to an expert centre, usually with a view to surgery, otherwise a PET scan will be requested [3]. In the rare cases where surgery is not performed, follow-up imaging by non-injected CT or MRI at 6-12 months is recommended.
3.1.1.1.2. Radiological appearance. Regardless of size, any adrenal mass that radiologically causes a suspicion of malignancy (local infiltration, suspected extra-adrenal metastasis) should warrant a multidisciplinary discussion in an expert centre, for its management, prior to excision.
ACCs may contain calcifications and more rarely fatty inclusions, as do certain adenomas and myelolipomas [32]. They frequently contain areas of necrosis and heterogeneous enhancement [10].
Positive diagnosis on imaging Homogenous/≤10UH
regardless of size
Stop assessment +/- surveillance
Complementary immaging or CTscan 6-12 months Laproscopy if ≥ 5mm
Non-suspect
< 4 cm et 10<UH≤20
non secretary Al
Unspecified diagnosis
< 4 cm et >20 UH
referrral in expert centrefor complementary imaging or adrenalectomy
Malignancy suspected or
< 4cm et hétérogène
Heterogenous ≥ 4cm or
≥ 4cm et 10<UH≤20
Al (CTscan)
Hormone assessment
Homogenous ≥ 4cm + >20UH
oncological history
Asymptomatic
MACS benign mass
Specific MDT meeting
FDG PET +/-Biopsy
Non-suspect
Symptomatic
Oncological MDT meeting if metastasis
Laprosscopic adrenalectomy
young with comorbidities
local invasion
Surénalectomie ouverte
IS sécrétant
indeterminated
≤ 6cm Laproscopic adrenalectomy
No local invasion
> 6cm individual surgery strategy
Suspect de malignité
Suspected MPC
Specific algorythm
Suspected ACC
Specific algorythm
Low risk of recurrence ENSAT 1-2 + Ki67≤10%
Surveillance
ACC < 4cm
Adrenalectomy (laparoscopic)
RO
Intermediate risk ENSAT 1-2+10<Ki67<20%
Managment in expert centre (Mitotane)
Localized stages (ENSAT 1-3) referred in expert centre
Surgery RO et LDN
High risk ENSAT 3 + Ki67>20%
Managment in expert centre [Mitotane ± radiottt)
MDT meeting in referral centre (Mitotane ± radiottt)
ACC ≥ 4cm
Open Adrenalectomy
R1 or Rx
Open adrenalectomy RO + LDN + focal therapy for métastasis
Resecable metastatic stages referred in expert centre
MDT meeting in referral centre (Mitotane ± radiottt)
Suspicion of ACC
FDG PET
R1 or Rx
Open adrenalectomy RO + LDN + métastasectomies
Follow-up every 2 months [imaging + hormone assessment)
Mitotane + focal therapy
Never néoadjuvant therapy
Follow-up every 2 months imaging + hormone assessment
ENSAT 3 and 4 non resecables referred in expert centre
Systemic therapy (Mitotane + chemottt)
2nd Line chemotherapy or clinical try
Debulking if uncontroled symptoms
2nd Line chemotherapy or clinical try
Systemic therapy (Mitotane + chemottt)
Follow-up every 2 months (imaging + hormone assessment)
Recurrence after Mitotane
Follow-up every 2 months (imaging + hormone assessment)
Mitotane + focal therapy
RO
Lifelong monitoring of métanephrines
resecable
Surgery
R1
Surveillance (clinic + paraclinic)
R2 (COMETE MDTM)
Surveillance or surgery +/- radioisotope therapy
Locally advanced PC
Slow evolution
Surveillance or loco- regional therapy
Treatment of complications (HTN, diabete, constipation) with antisecretant if necessary
Non resecable or non operable
Surveillance (scalability volume, secretion)
Radioisotope therape
Failure
Suspicion ofMPC
nuclear Imaginig
Rapid evolution or decision of ttt by COMETE MDTM
Systemic therapy (Sunitinib +/- chemotherapy)
Surgery + focal therapy for métastasis
curable et operable Oligometastatic
Clinical try
Surgery + métastasectomies
local therapy for tumour + focal therapy for metastasis
PCM (metastatic)
Oligometastatic
Surveillance and palliative care
Focal therapy for metastasis if necessary
Non operable and non resecable
Radioisotope therapy
Systemic therapy
Polymetastatic
Clinical try
Adjuvant therapy +/- radioisotope therapy
Surveillance and palliative care
Uncontroled hormonal symptoms
Debulking
Clinical try
Surveillance and palliative care
From a CT scan point of view, there is no criterion for differentiating between PCs associated with symptoms and those that are clinically silent.
3.1.1.1.3. Hormonal activity. Hormonal activity manifest or pauci- symptomatic adrenal hypersecretion is an indication for surgery, after endocrinological confirmation.
When it is clinically silent, multidisciplinary discussion is warranted before excision. For benign adrenal mass with mild autonomous cortisol secretion (MACS), surgery is not routinely recommended. Several studies show that progression to full-blown Cushing’s syndrome occurs in less than 1% of patients [3]. Patients who are not treated surgically should undergo an annual clinical examination to detect the appearance or worsening of associated comorbidities.
Laparoscopic adrenalectomy may be discussed from the outset for MACS in young patients with metabolic comorbidities potentially attributable to cortisol (hypertension, NIDDM and vertebral fractures) [3].
In cases of primary hyperaldosteronism (suspected Conn’s adenoma), venous sampling by catheterisation of the adrenal vein is recommended [3]. This may be necessary to confirm the lateral location of aldosterone hypersecretion on the side of the adrenal lesion.
Recommendation Table 5
3.1.1.2. Surgical technique.
3.1.1.2.1. General principles. Adrenalectomy of AI should in principle, be oncological without rupture of tumor capsule.
3.1.1.2.2. Approach. A laparoscopic approach is recommended if the tumour is unilateral ≤6 cm and there is no evidence of invasion into adjacent structures.
A laparoscopic approach is contraindicated in cases of suspected malignancy. It may be considered on a case-by-case basis in referral centre with an expert high-volume adrenal surgeon. Defining an expert centre remains tricky in the absence of studies on the results of surgery as a function of volume.
With a laparoscopic excision, the gland and peri-adrenal fat are removed en bloc via a retrieval bag.
If there is any doubt about local invasion, a risk of rupture of tumor capsule or incomplete resection, laparotomy is recommended immedi- ately or by early conversion [3,9].
3.1.2. Monitoring
In 2019, there was a meta-analysis involving 4121 patients with nonfunctioning adrenal lesions, the mean tumour growth was 2 mm over a median of 52.8 months of follow-up; only 2.5% of the patients had a tumour progression of 1 cm or more, and no adrenocortical carcinoma developed in any of the patients [33].
3.1.2.1. Indications and procedures. Patients with unspecified AI who do not undergo surgical resection de novo should be monitored [3,9].
The recommended intervals for noncontrast CT or MRI are 6 and 12 months.
Any progression in a volume of more than 20% or in a major axis of more than 5 mm during this interval should lead to adrenalectomy. Progression below this threshold in an indication for additional imaging between 6 to 12 months [3,9].
The AUA recommends stopping surveillance in the event of progression of less than 3 mm [7].
Recommendation Table 6
Recommendation Table 5
| Management guideliness | Grade |
|---|---|
| Homogeneous IS with a normal hormone profile and a CT scan with a density of HU < 10, with homogeneous parenchyma and rapid wash-out is considered to be a benign adenoma. - < 4 cm: assessment and monitoring discontinued in the absence of clinical progress. - ≥ 4 cm: Monitoring by non-injected CT scan at 6-12 months | High |
| Homogeneous IS < 4 cm, spontaneous density HU 11-20 with a normal hormonal balance: - Carry out additional imaging immediately or - Follow-up at 12 months with non-injected CT (or MRI). | Low |
| IS ≥ 4 cm heterogeneous or ≥ 4 cm homogeneous unenhanced but HU > 20 (suspected malignancy) : - Perform an extension work-up (thoracic CT and/or FDG PET/CT) - Transfer to an expert centre for RCP and probable surgery. - If surgery is not performed, follow-up imaging in 6 to 12 months is recommended. | Low |
| Other cases of IS (IS ≥ 4 cm with density + HU 11 -20 without enhancement; or AI<4 cm + HU> 20 ; or IS <4 cm but heterogeneous): | Low |
| - Individualized approach with discussion in RCP (probability of a malignant tumour still low). - Immediate additional imaging preferred, followed by surgery or - After AI still considered indeterminate: surgery or new imaging at 6 to 12 month intervals (non-contrast CT/MRI). |
AI: adrenal incidentaloma; CT: computed tomography; HU: Hounsfield units; MRI: magnetic resonance imaging, AM: adrenal metastasis.
Recommendation Table 6
| Surgical indication for an AI | Grade |
|---|---|
| - < 4 cm initially + HU 11- 20 with growth on surveillance imaging (6-12 months) > 5mm or >20%. If growth is below this threshold, imaging at 6 to 12 months may be considered. | High |
| - ≥ 4.0 cm + HU > 20 or ≥ 4.0 cm + heterogeneous Referral to an expert centre after MDT meeting | High |
| - Accompanied by a clinically significant hormonal excess. A minimally invasive approach is recommended after discussion in the MDT meeting. | High |
| - If there are clinical, radiological or hormonal signs of malignancy suggestive of adrenal cancer ≤ 6 cm and no signs of local invasion, the minimally invasive approach may be considered by an experienced surgeon, in an expert centre following a MDT meeting. | High |
HU: Hounsfield units; MDT: multidisciplinary team.
3.1.2.2. No indications. When a nonsecretory AI is benign on initial imaging (Table 3) and regardless of its size:
· no complementary exploration is warranted [30];
. no monitoring is recommended in the absence of clinical progression [34] or worsening of existing comorbidities (hypertension, NIDDM). In the case of a size > 6 cm, this decision will be is verified via MDTM.
3.2. Suspected ACC
A suspicion of the ACC is based on a number of arguments at the initial work-up. A diagnosis of certainty will be subsequently made (anatomo- pathology and follow-up).
3.2.1. Indications
Surgery is indicated for any localised form, when an R0 resection can be envisaged in more than 95% of cases, with a mortality risk of less than 5%, and a risk of morbidity that does not preclude rapid adjuvant treatment (mitotane) postoperatively (ideally less than six weeks). This corresponds to half of all the cases (all stages 1s and 2s according to ENSAT [see Section 4.1.2] and most stage 3s) [10].
If complete resection is not possible, consider neoadjuvant treatment (e.g. mitotane plus cisplatin or EDP).
Surgery must be carried out within 4 weeks in accordance with the principles of carcinological surgery, i.e. complete removal without rupture tumor capsule. It should be performed in a centre with expertise in adrenal oncological surgery. International recommendations suggest a threshold of 7 to 15 procedures per year to identify an expert centre [10].
For metastatic forms, treatment is based on mitotane and sometimes chemotherapy. Surgical resection of the primary tumour and any metastases may be considered if the primary tumour is > 60-80% of the tumour mass, if R0 resection is feasible, and if the risk of mortality is < 5%.
Medical treatment of hormonal hypersecretion is sometimes a preoperative therapeutic emergency. Its aim is adrenal insufficiency in order to reduce the mortality induced by these secretions. Although the best strategy is still poorly understood, the routine “block and replace” strategy is recommended, particularly in cases of neoplastic emergencies. The COMETE recommendations detail this antisecretory management [10] Abiraterone’s ability to suppress cortisol and androgens can be exploited in patients with secreting ACC. It has therefore been added to the antisecretory armoury of ACC associated with Cushing’s syndrome [10].
3.2.2. Surgical technique
3.2.2.1. General principles. The absence of a positive margin, capsular effraction or any other event with a risk of dissemination is crucial in these
stages, which can be cured by surgery alone [35]. Sacrifice of adjacent structures is not justified as long as the resection meets these requirements [36,37] and does not affect survival in localised stages.
Lymphadenectomy is recommended for staging purposes, as lymph node status is a major prognostic factor. This should include at least the peri-adrenal and perirenal lymph nodes, as well as those in the renal hilum. More extensive lymph node dissection (celiac, superior mesenter- ic, homolateral para-aortic or para-caval and interaortic-caval) is sometimes proposed but is based on a lower level of evidence. In all cases, all adenopathies suspected preoperatively or intraoperatively should be resected [10].
3.2.2.2. Approach. Despite the lack of randomised trials, by consensus, laparotomy is recommended for known or suspected ACC [24,31].
A subcostal incision is the preferred approach [38].
Minimally invasive approaches (e.g. laparoscopy, retroperitoneoscopy, robotic approaches), the new standard for benign tumours, have been described for ACC. Some retrospective laparoscopic studies have even reported specific and recurrence-free survival rates comparable to those of laparotomy surgery [39]. Others suspect that a laparoscopic approach may have a negative impact on overall survival from Stage 2 onwards [38].
Given the aggressive nature of ACC and the extremely poor prognosis of R1 resection or rupture of tumour capsule, laparoscopy should never be “attempted” if a risk of conversion is envisaged preoperatively. Calcatera series [40] showed that conversion to laparotomy decreased survival (60% survival at 1 year compared to 80% in case of a total laparoscopic procedure).
Transperitoneal laparoscopy in the lateral decubitus position is only possible under the following conditions [10]:
· small tumours (< 4 cm) and;
· not clearly malignant on preoperative hormonal and radiological tests (pure cortisol secretory profile, HU ≤ 10 or tissue homogeneity, no invasion of adjacent organs) and;
· examination in a centre that is either highly experienced in adrenal carcinological excision. We recommend that laparoscopic approach is performed by an expert high-volume adrenal surgeon;
· the excision must be the same as that which would be performed by laparotomy (extended fat removal, lymphadenectomy) and;
· the part is extracted in a bag without breaking it up (analysis of the margins is essential), and;
· the case is recorded prospectively in the ENSAT database.
Robotic transperitoneal adrenalectomy has the same indications, advantages and limitations as conventional laparoscopy [41]. Retro- peritoneoscopy is formally contraindicated in cases of suspected ACC, even of less than 4 cm [31].
For suspected ACCs >6 cm, ENSAT contraindicates laparoscopy [10,31] because of more frequent and earlier local recurrence [42].
3.3. Pheochromocytomas
3.3.1. Indication
Adrenalectomy should be validated in a specialized MDTM.
It should be performed by a surgical and anaesthetic team trained in the management of adrenal secretory syndromes to ensure perioperative mortality of less than 3% [43].
If MPC is suspected, the treatment is usually multimodal. Surgery will be considered only if complete surgical excision of the adrenal gland or even the metastases is possible.
3.3.2. Surgical technique
3.3.2.1. General principles. Adrenalectomy, regardless of the approach, is in principle carcinogenic (total adrenalectomy removes its cellulo-fatty atmosphere if possible, without rupture of tumour capsule … ). It is recommended to extend the resection to the peri-adrenal fat as the
prognosis for patients with PC is difficult to assess. However, sacrificing adjacent structures is not recommended in case of non-suspect PC.
Malignant forms (10-20%) evolve relatively slowly, making an R1 excision over a small area preferable to a procedure with a risk of morbidity or long-term functional sequelae.
The main adrenal drainage vein should be ligated/sectioned as soon as possible to limit catecholaminergic release and therefore intraoperative blood pressure fluctuations [44].
After removal of the tumour, a major decrease in BP can be observed. Therefore, this surgical procedure requires close collaboration with an experienced anaesthetist who is prepared to adress frequent and sudden perioperative haemodynamic fluctuations.
In case of MPC, the aim of surgery is macroscopically complete removal of all tumour locations within negative margins (adrenal and metastatic). Sacrifice of adjacent organs is indicated if there is any doubt of neighbouring invasion. The indication for routine lymphadenectomy is debated and it cannot be recommended in current practice even in case of MPC [45].
3.3.2.2. Approached routes. According to a multicentric study, the risk factors for conversion from laparoscopy to laparotomy are a tumour size >6 cm and a significant number of intraoperative hypertensive episodes > 200 mmHg [46].
The expert opinion is that the 6 cm threshold would therefore be a reasonable limit for the laparoscopic approach [47].
3.3.2.2.1. Approach for non-suspected PC (no evidence of malignancy). When possible/reasonable, laparoscopy allows less tumour mobilisation, which limits blood pressure fluctuations and accelerates recovery [48].
Two laparoscopic approaches are then possible: the transperitoneal approach in the lateral decubitus position, which is the most common, possibly robot-assisted method [11] and the retroperitoneal route. The transperitoneal approach is preferred because the usual anatomical landmarks of digestive and endocrine surgeons are the ones used, conversion to laparotomy is easier and exposure is possible by mobilizing adjacent organs. Retroperitoneoscopy is feasible even though one retrospective study showed that episodes of arterial hypotension (mean arterial pressure < 60 mmHg) were more frequent than with anterior laparoscopy [44], although advances in medical preparations (calcium channel blockers, alpha-adrenergic blocking agents) and anaesthetic protocols are improving these intraoperative blood pressure fluctuations.
In case of a large PC (usually >6 cm), a laparotomy de novo is recommended. The limit is, in practice, between 5 and 7 cm (depending on the teams, the experience of the operator and the morphotype of the patient) [46].
3.3.2.2.2. Approach in case of suspected PCM. In the case of metastatic MPC, laparotomy is recommended [46] in order to minimize the risk of rupture of the tumour capsule and to be able to perform a complete excision (R0) guided by preoperative imaging and intraoperative findings.
3.4. Adrenal metastases
Solitary adrenal metastases are often confined to the adrenal gland. Laparoscopic adrenalectomy is a safe technique for excision with healthy margins, while reducing morbidity. If there is evidence of surrounding tissue invasion intraoperatively, the procedure should be converted to a laparotomy [49].
4. Postoperative oncological diagnosis
4.1. ACC
4.1.1. Pathological diagnosis: multiparametric scores
If there is any doubt as to whether or not the tumour is of cortical origin, an immunohistochemical examination of steroidogenic factor-1 (SF-1) expression should be routinely performed because it is the most sensitive and specific adrenal cortex marker [50].
In proven ACC, the pathological examination is crucial. It is used to establish the pTNM stage, and the “R” resection status and to calculate a multiparametric score on which the diagnosis of malignancy is based [10]. Currently, the most widely used score is the Weiss histoprognostic score [51]. It is based on 9 criteria rated 0 or 1. Malignancy is diagnosed when a localised tumour has a Weiss score ≥ 3 and/or in the event of a local invasion or distant metastases [1,31].
Other scores have been validated, particularly when the Weiss score is unsuitable (e.g. Lin Weiss Bisceglia score [52] or Helsinki score [53]).
In case of a doubtful diagnosis of ACC, a centralised rereading of the slides should be performed within the COMETE network. Double reading is recommended within the network.
4.1.2. TNM and ENSAT classification
In case of preoperative suspicion, the cTNM stage is assessed preoperatively and is useful for therapeutic management. The 8th edition of the TNM (2016) is authoritative (Table 4) [54]. The pTNM is postoperative. It is a major prognostic factor for relapse and survival in ACC patients.
The ENSAT classification [31] has prognostic value:
· stage 1: T1 NO MO;
· stage 2: T2 NO MO;
· stage 3: T1/2 N1 M0 or T3/T4N0/1 MO;
· stage 4: T1-4 NO-1 M1.
4.1.3. Other histological prognostic factors
The resection status (“R”) of the primary tumour.
Ki-67 cell proliferation index assessment by immunohistochemistry
After R0 resection, an index < 10% corresponds to a low risk of recurrence (without the need for adjuvant therapy). A Ki-67 index of > 20% indicates a high risk of recurrence (even R0, adjuvant therapy is recommended). A Ki-67 index between 10 and 20%, regardless of the stage or R status, indicates an intermediate risk of recurrence.
Advanced age [10,55] and cortisol secretion [56] appear to be associated with a bleaker prognosis.
4.2. MPC
In general, the histological diagnosis of PC is not problematic, but the criteria for malignancy are debated [57]. At present, the only formal proof of malignancy is the invasion of adjacent organs or distant metastases [57,58]. In theory, all PCs have the potential to be malignant [59].
| Stage T (Primary Tumor) | |
| Tx | Primary tumour cannot be assessed |
| T0 | No evidence of primary tumour |
| T1 | Tumour ≤5 cm in greatest dimension, no extra-adrenal invasion |
| T2 | Tumour >5 cm in greatest dimension, no extra-adrenal invasion |
| T3 | Tumour of any size with local invasion but not invading adjacent organs |
| T4 | Tumour of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) and large blood vessels (hepatic vein or vena cava) |
| Stage N (regional lymph nodes: hilar, abdominal paraaortic and paracacal nodes) | |
| Nx | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in regional node(s) |
| Stage M (distant metastasis) | |
| cM0 | No distant metastasis |
| cM1 | Distant metastasis |
| pM1 | Histologically confirmed distant metastasis |
| Stage R (residual tumor) | |
| Rx | The presence of residual tumor cannot be assessed |
| R0 | No residual tumor |
| R1 | Microscopic residual tumor |
| R2 | Macroscopic residual tumor |
In practice, vascular or capsular invasion, and necrosis or mitosis are the criteria associated with a high risk of malignancy without being systematically associated with metastases.
In other cases, there are several scores to assess the risk of malignancy, although they are not validated [60]. The most widely used score is the Pheochromocytoma of the Adrenal Gland Scale (PASS) score [23]. This score is based on 12 histological parameters and is given a score of 20 points. A score of less than 4 indicates benign disease, whereas a score of more than 6 indicates malignant disease. More recently, the grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score, which is common to pheochromocytomas and paragangliomas, has been used to define metastatic risk [11,58].
4.3. Adrenal metastasis
Primary cancers are mainly lung cancer (35%), kidney cancer, breast cancer, malignant melanoma, stomach cancer, colorectal cancer and lymphoma. Isolated adrenal location is rare, but it often remains confined to the gland, hence, excision surgery is important [1].
Adrenal metastases are classified as M+ in the TNM classification of the primary cancer.
Recommendation Table 7
Recommendation Table 7
| TMS generalities | Grade |
|---|---|
| A definitive diagnosis of SCC is histological, enabling the TNM classification and ENSAT stage to be established. The Ki-67 pathology index is used for prognostic purposes and to guide further treatment. | High |
| For PC: there are no specific histological criteria for malignancy, apart from invasion of adjacent organs or metastasis. | High |
| For PC: capsular invasion and vascular invasion are inconsistent risk factors for malignancy. The PASS score is imprecise and although its use is not recommended in current practice, it is the most commonly used score for diagnosing MPC. | Low |
| There is no TNM classification for MPC. | High |
5. Oncological follow-up
5.1. ACC
After a complete resection, lifelong follow-up by clinical and radiological assessment (TAP scan or abdominal MRI combined with chest CT or 18FDG PET scan) is recommended.
Recommendation Table 8 Summary of diagnostic and therapeutic guidelines for malignant adrenal tumors.
| Managment | Adrenocortical carcinoma | Malignant pheochromocytoma | Adrenal Metastasis | Level of evidence |
|---|---|---|---|---|
| Diagnostic recommendations | ||||
| Clinic | Interview (PFS, symptoms, genetic contex) | Interview (PFS, symptoms, genetic context) | Interview (PFS, symptoms, other secondary locations) | High |
| Organic | Adrenocortical hormone assessment | Adrenomedullary hormone assessment | According to the primary tumour (markers) | High |
| Biopsy | No | Contraindicated | Positive diagnosis | High |
| Imaging | CTscan/MRI 18 FDG PET | CTscan/MRI PET68 Ga DOTATOC or18 FDOPA depending on the context | CT Scan 18FDG PET | High |
| Treatment recommendations: localized stages | ||||
| 1ère intention | Adrenalectomy within healthy margin + LDN +/- antisecretant therapy | Adrenalectomy within healthy margin +/- antisecretant therapy | Adrenalectomy or focal therapy | Low |
| Additive | - RO: Surveillance for low risk, Mitotane for intermediate risk, Mitotane ± radiotherapy for high risk. - R1 or Rx : Mitotane ± radiotherapy | Radioisotope therapy | According to the primary tumour | Low |
| Therapeutic recommendations: metastatic stages | ||||
| 1ère intention | Complete resection in healthy margins (or focal treatment) of all sites + LDN | Complete excision of all locations with healthy margins +/- antisecretant therapy | Complete excision of all secondary locations of the primary tumour | Low |
| Alternative | Systemic treatment (mitotane, chemotherapy) +/- focal trherapy of metastases or clinical trial | Focal therapy of metastases Monitoring (slow progression) Metabolic radiotherapy Chemotherapy Anti-angiogenic | Systemic treatment of primary disease | Low |
| Follow-up recommendation | ||||
| Follow-up | Hormone check-up CTscan/18FDG PET | Urinary metanephrines for life +/- 18FDOPA PET +/- 68Ga DOTATOC PET | Primitive function +/- 18FDG PET | Low |
PFS: performance status; CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography; 18FDG: fluorodeoxyglucose (18 F); F-DOPA: fluoro-18-L-dihydroxyphenylalanine; R0: no residual tumour; R1: microscopic tumour remnant; Rx: tumour remnant that cannot be assessed; 68Ga-DOTATOC: somatostatin receptor specific marker.
The modalities are adapted to the risk of relapse although no monitoring frequency is validated. For the first two years, surveillance is usually every 3 months. It is then at a frequency which is appropriate to the risk. After 10 years of surveillance with negative results, patients are monitored at least every 5 years.
After a secretory ACC, a regular hormonal test should be performed [31].
5.2. MPC
MPCs are monitored for life, as there can be a recurrence very late in life. Most of the times, it is based on plasma or urine metanephrine measurements alone, but some combine this with imaging [61].
Most authors recommend only annual measurements of metanephr- ines [11].
In metastatic patients, morphological assessments by CTscan and/or MRI are repeated every three months during the treatment phase and then every three to twenty-four months depending on the case.
Monitoring methods for metastatic patients include clinical monitor- ing, monitoring of hormonal markers and targets, and the most effective preoperative imaging methods (conventional or nuclear medicine) [11].
5.3. AM
The eradication of AM does not influence the specific follow-up of the primary cancer.
Recommendation Table 8
6. Conclusion
Any AI requires a first-line work-up, at least clinical and endocrine, even if there is a suspicion of secondary involvement. An asymptomatic, nonfunctional unilateral AIs with benign features detectable on imaging should not be treated surgically.
Any unilateral AI of undetermined origin and larger than 4 cm should be treated surgically, usually via laparoscopy. Adrenalectomy is also the treatment of choice for unilateral AIs suspected of being malignant or secreting. For any AI, in principle, surgical treatment should be oncological.
AIs are frequent but rarely malignant. Therefore, the highly specific treatment of malignant neoplasms of the adrenal gland justifies their referencing at the COMETE network in France (Appendix 1). Manage- ment varies according to the diagnostic orientation (Recommendation Table 8). As for any rare disease, management in an expert centre is recommended.
Disclosure of interest
The authors declare that they have no competing interest.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.fjurol.2024.102748.
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