ESE Diagnosis Recommendations

This section details the key recommendations of the European Society of Endocrinology (ESE).

All patients with suspected and proven ACC should be discussed in a multidisciplinary expert team meeting (including health care providers experienced in the care of adrenal tumours, such as those who work in endocrinology, oncology, pathology, radiology and surgery), at least at the time of initial diagnosis (Fassnacht et al., 2018).

It should be established whether an adrenal mass is malignant as soon as possible, using suitable diagnostic tools in a timely manner (Fassnacht et al., 2018).


How do you unlock an ACC diagnosis?

How do you unlock an ACC diagnosis?

Clinical assessment

Every patient with suspected ACC should undergo careful assessment. The patient’s case history and a clinical examination for symptoms and signs of adrenal hormonal excess should be prioritised (Fassnacht et al., 2018).


Patients should be evaluated for:

Areas of evaluation for the clinical assessment of adrenocortical carcinoma.

Any evidence of co-secretion of different steroids raises the suspicion of ACC (Fassnacht et al., 2018).

Hormonal work-up

All patients with suspected ACC should undergo a detailed hormonal work-up to identify potential autonomous excess of glucocorticoids, sex hormones, mineralocorticoids and adrenocortical steroid hormone precursors (Fassnacht et al., 2018).

A phaeocytochroma must be excluded (Fassnacht., 2018).


The following work-up should be carried out in patients with suspected ACC (Fassnacht et al., 2018):

Table 2. Hormonal work-up.

Hormonal work-up

ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulphate.

Why are detailed hormonal work-ups so important? (Fassnacht et al., 2018)

Why are detailed hormonal work-ups so important?


Imaging

Adrenal-focused imaging should be carried out in all patients with suspected ACC (Fassnacht et al., 2018).

A chest CT plus abdominal-pelvic cross-sectional imaging (CT or MRI) in patients where there is a high suspicion of ACC (Fassnacht et al., 2018).


Additional imaging (such as bone and brain imaging) should be performed in the case of clinical suspicion of metastatic lesions (Fassnacht et al., 2018). The following imaging methods should be used in patients with suspected or proven ACC (Fassnacht et al., 2018):

Table 3. Imaging in patients with suspected or proven ACC (Fassnacht et al., 2018).

Imaging in patients with suspected or proven ACC

CT, computed tomography, FDG/PET, Fluorodeoxyglucose positron emission tomography, MRI, magnetic resonance imaging. *The panel did not agree on the systematic use of FDG-PET/CT4.

The following imaging features can differentiate ACC from ACA:

Table 4. Lesion characteristics (Else et al., 2014).

Lesion characteristics

ACC, adrenocortical carcinoma; ACA, adrenocortical adenoma; HU, Hounsfield units; SUV, standardised uptake values.

Other points to consider are (Fassnacht et al., 2018):

  • CT, MRI and FDG-PET/CT are the main techniques used for the differentiation of benign and malignant tumours.
  • Only non-contrast CT is considered by the ESE to be sufficiently reliable to rule out ACC when the non-adrenal mass is homogenous and has low CT density (≤ 10 HU).
  • FDG-PET/CT is mainly used to detect malignant disease; CT and MRI are usually used to exclude malignancy.
  • The presence of metastases must be evaluated before any treatment is initiated.
  • No single imaging method can definitively prove the diagnosis of ACC – the pros and cons of each method should be evaluated.

Pathological work-up

The diagnosis of ACC should be performed by histopathology (Fassnacht et al., 2018).


Histopathology is the gold standard of diagnosing ACC and should be obtained in all patients in principle (Fassnacht et al., 2018):

  • in operable patients, histopathology should be done on the resection sample.
  • in inoperable patients, histopathology should be done on a biopsy sample (taken in accordance with good oncological practice).

Adrenal biopsy should NOT be used in patients with suspected ACC unless there is evidence of metastatic disease that precludes surgery and histopathological proof is required to inform oncological management (Fassnacht et al., 2018).


Differentiating benign from malignant adrenocortical tumours by biopsy alone may lead to misdiagnosis (Fassnacht et al., 2018). Biopsies also create a risk of haemorrhaging and other complications such as pneumothorax, pancreatitis, adrenal abscess, bacteraemia and needle-tract metastasis (Williams et al., 2014).

  • ESE suggest that all adrenal tumours and suspected ACCs should be reviewed by an expert adrenal pathologist as misdiagnosis is common and challenging (Fassnacht et al., 2018).
  • ESE also suggest that immunohistochemistry for steroidogenic factor-1 (SF-1) is used to differentiate primary adrenocortical tumours from non-adrenocortical tumours - SF-1 is the most sensitive and specific marker currently available to establish if a tumour is of adrenocortical origin (98% sensitivity; 100% specificity), if SF-1 is not available, a combination of markers including inhibin-alpha, Melan-A and calretinin is advised (Fassnacht et al., 2018).

Use the Weiss system to distinguish benign from malignant tumours (Fassnacht et al., 2018).

Weiss system criteria (Kassi et al., 2016; Fassnacht et al., 2018).

Figure 2. Weiss system criteria (Kassi et al., 2016; Fassnacht et al., 2018)

  • Each criterion met adds 1 point to the Weiss score (Williams et al., 2014; Fassnacht et al., 2018).
  • A Weiss score of 3 or higher (out of the 9 criteria) indicates ACC (Fassnacht et al., 2018).
  • A Weiss score of 2 or 3 may sometimes be considered borderline between benign and malignant (Fassnacht et al., 2018).

Ki67 immunochemistry has been proposed for prognostic purposes. It should be used for every resection specimen of an adrenocortical tumour (Fassnacht et al., 2018).


High Ki67 levels are associated with poor prognosis. Threshold levels of 10% and 20% have been considered for discriminating low from high Ki67 levels and patients with Ki67 >10% are considered to have a high risk of recurrence following radical resection (Fassnacht et al., 2018). As Ki67 labelling is unevenly distributed, determination of the Ki67 index should be done on whole tumours – with particular attention to areas of higher proliferation (Fassnacht et al., 2018).

The pathophysiology report of a suspected ACC should at least contain: Weiss score (including the exact mitotic count), exact Ki67 index, resection status and pathological tumour stage (indicating invasion or not of the capsule and/or surrounding tissue and organs) and nodal status (Fassnacht et al., 2018).


Staging classification and prognostic factors

The European network for the study of adrenal tumors (ENSAT) staging classifications should be used at the time of initial diagnosis (Fassnacht M et al., 2018):


Table 5. Tumour stage – ENSAT classification.

Tumour stage – ENSAT classification

T1: tumour ≥5cm; T2: >5cm; T3: infiltration into the surrounding tissues; T4; tumour invasion into adjacent organs or venous tumour thrombus in vena cava or renal vein; N0; no positive lymph node; N1; positive lymph node; M0; no distant metastases; M1; presence of distant metastases.

At initial diagnosis, the following prognostic factors should be taken into account: tumour stage, resection status, Ki67 index (or mitotic count), autonomous cortisol secretion and the patient’s general condition (Fassnacht et al., 2018).

Points to consider (Fassnacht et al., 2018):

  • In patients with a localised (stage I‒III) disease, the main prognostic factors are: tumour stage, resection status and Ki67 labelling index.
  • In patients with advanced disease (stage IV or recurrent disease not amenable to complete resection or R2 resection), high tumour burden, high tumour grade, high Ki67 index and uncontrolled symptoms are a major focus associated with worse prognosis.

ESE Treatment Recommendations References
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