Registry and Biobank of the European Network for the Study of Adrenal Tumours (ENS@T)

Adrenal tumours
Tumours of the adrenal glands arise from the cortex or the medulla part of the
adrenal gland. Clinical manifestations arise because of symptoms from excess
secretion of hormones by the tumours. The tumours from the adrenal cortex can
produce excess of steroid hormones including cortisol and aldosterone and
tumours from the adrenal medulla can produce excessive amounts of
catecholamines. Malignant adrenal tumours can also manifest through local mass
effects or symptoms related to distant metastatic spread. Adrenal tumours can
be benign or malignant. Often this separation is difficult to make and
long-term close follow up is necessary after surgical removal to detect
recurrences early in patients who have adrenal cancer. While malignant tumours
of the adrenal gland are rare, up to 3.5% of the population have so called
adrenal incidentalomas - tumours of the adrenals found incidentally during
investigation for an unrelated condition. The majority of these do not secrete
hormones (1).

Aldosterone Producing Adenoma
Primary aldosteronism is the most frequent form of secondary hypertension
accounting for more than 11% of referred hypertensive patients (2). Although it
is usually held to be caused by bilateral idiopathic hyperplasia in
approximately two-thirds of cases and aldosterone-producing adenoma (Conn's
syndrome) in one-third, these relative rates are reversed when adrenal vein
sampling is systematically used (2). Hence, primary aldosteronism due to
adrenal tumours is likely the most common form of the disease. However, many
experts now contend that there could be a continuum between bilateral
adrenocortical hyperplasia and unilateral aldosterone-producing adenoma. Of
note, notwithstanding the high prevalence of primary aldosteronism the
molecular mechanisms underlying excess aldosterone production in this continuum
remain totally unknown. Therefore, the availability of a large collection of
aldosterone-producing tumours would be instrumental for allowing investigating
these molecular mechanisms through application of novel techniques for the
analysis of the whole transcriptome (3), the microRNA profile and the proteome.
In its classical form, primary aldosteronism presents with aldosterone excess,
low plasma renin activity, while hypokalemia, once assumed to be a hallmark of
the syndrome lacks in most cases. Patients with aldosterone producing adenomas
have more severe hypertension, more frequent hypokalemia, higher plasma and
urinary levels of aldosterone, and are younger than those with bilateral
disease. Once primary aldosteronism is confirmed, the subtype needs to be
determined to guide treatment. Computed tomography or magnetic resonance
imaging are required to detect the adenoma or and aldosterone-producing
carcinoma, but give misleading results in terms of identifying the unilateral
or bilateral source of excess aldosterone (4, 5). Hence, to pose the indication
for adrenalectomy most patients require adrenal vein sampling (5). Optimal
treatment for aldosterone-producing adenoma or unilateral hyperplasia is
unilateral laparoscopic adrenalectomy.

Pheochromocytomas and Paragangliomas
Catecholamine-producing tumours may arise in the adrenal medulla
(pheochromocytomas) or in extra-adrenal chromaffin cells (paragangliomas).
Their prevalence is about 0.2% in patients with hypertension (6-8) and 4% in
patients with a incidentally discovered adrenal mass (9).
These tumours may be sporadic or may present as part of any of several genetic
syndromes: familial pheochromocytoma-paraganglioma syndromes, multiple
endocrine neoplasia type 2, neurofibromatosis 1, and von Hippel-Lindau disease.
Familial cases are diagnosed earlier and are more frequently bilateral and
recurrent than sporadic cases. The most specific and sensitive diagnostic test
for the tumour is the determination of plasma or urinary metanephrines. The
tumours can be located by computed tomography, magnetic resonance imaging and
metaiodobenzylguanidine scintigraphy. Treatment is resection of the tumour,
usually by laparoscopic surgery.
About 10% of tumours are malignant either at first operation or during
follow-up, malignancy being diagnosed by the presence of metastases at sites
where chromaffin cells should be normally absent (i.e., bones, liver, lungs,
lymphnodes). Recurrences and malignancy are more frequent in cases with large
or extra-adrenal tumours. Treatment for malignant recurrence includes surgery,
therapeutic embolization, chemotherapy and metabolic radiotherapy (10).
Patients, especially those with familial or extra-adrenal tumours, should be
followed-up indefinitely.

Non-aldosterone cortical adrenal adenomas
Non-aldosterone secreting cortical tumours represent the most common benign
adrenal tumour. These may be truly non-functioning, that is not associated with
any hormonal excess, and are usually detected incidentally in patients
undergoing radiological investigations (ultrasound, CT, MRI scanning) for other
reasons. Indeed, autopsy studies have shown that up to 5% of the population may
harbour so-called adrenal "incidentalomas". Malignancy rate in these lesions is
very low - the majority of lesions are less than 3cm in diameter and can be
treated conservatively (11).
Rarely the tumours may secrete cortisol. In the most florid example, Cushing's
syndrome results because of severe hypercortisolism resulting in central
adiposity, muscle wasting, thinning of the skin with bruising, osteoporosis,
hypertension and diabetes mellitus. Removal of the adenoma is required to cure
the condition. More rarely patients may have a genetic problem that results in
autonomous production of cortisol from adenomas within the adrenals (e.g.
McCune Albright syndrome or Carney's complex). The adrenals may also become
hyperplastic or tumorous when the adrenal glands develop an unusual pattern of
receptor expression over and above the normal receptor that controls cortisol
production - the ACTH-receptor.
"Sub-clinical" Cushing's syndrome can also be found in patients harbouring
adrenal incidentalomas occurring in up to 10% of all cases. These patients may
have an increased risk of hypertension, obesity and diabetes.

Adrenocortical Carcinomas
Adrenocortical carcinoma (ACC) is a rare malignancy with incompletely
understood pathogenesis and poor prognosis. Patients present with hormone
excess (e.g. virilization, Cushing's syndrome) or a local mass effect (median
tumour size at diagnosis > 10cm). Tumours typically appear inhomogeneous in
both computerised tomography and magnetic resonance imaging with irregular
borders, and differ from benign adrenal tumours by their low fat content.
Hormonal analysis reveals evidence of steroid hormone secretion by the tumour
in the majority of cases, even in seemingly hormonally inactive lesions.
Histopathology is crucial for the diagnosis of malignancy and may also provide
important prognostic information. In stages I -III open surgery by an expert
surgeon aiming at complete resection is the treatment of choice. Local
recurrence is frequent, particularly after violation of the tumour capsule.
Surgery plays also a role in local tumour recurrence and metastatic disease.
In patients not amenable to surgery, mitotane as a substance with adrenolytic
properties remains the treatment of choice (12). Monitoring of drug levels is
mandatory for optimum results. In advanced disease, the most promising
therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane and
streptozotocin plus mitotane) are currently being compared in an international
phase III trial. Adjuvant treatment options after complete tumour removal (e.g.
mitotane, radiotherapy) are urgently needed, as postoperative disease free
survival at five years is below 50% (13).
*
European Network for the Study of Adrenal Tumours (ENS@T)
With the exception of endocrine inactive adenomas adrenal tumours are rare.
Therefore, progress in diagnosis and treatment of these tumour entities can
only be achieved by combining the efforts of researchers and clinicians from
several countries. To overcome these difficulties and to achieve significant
progress benefiting the affected patients a Network on Adrenal Tumours at a
European-wide level has been created.
The European Network for the Study of Adrenal Tumours (ENS@T) aims to improve
the understanding of the genetics, tumourigenesis and hormonal hypersecretion
in patients with adrenal tumours and associated familial syndromes. It intends
to improve the prediction of recurrence and the management of malignant adrenal
tumours, which are particularly rare. The study of adrenal tumours is likely to
reveal new molecular mechanisms of tumour growth and provide insight into the
role of hormones as the cause of hypertension.
ENS@T was founded in 2002 by putting together three already existing National
Adrenal Networks (COMETE in France, GANIMED in Germany, and NISGAT in Italy)
and teams from the United Kingdom all dedicated to the study of adrenal
tumours. In 2009, ENS@T became a membership-based society with statutes and
bye-laws (www.ensat.org).

A core part of the scientific efforts of ENS@T researchers bases on the
establishment of a common registry and associated collection of biomaterials.
Patients with adrenal tumours prospectively included in the ENS@T registry will
be asked to provide blood and urine samples and * as available * tumour
material collected during surgical resection.

The scientific aims of the proposed project can be summarized as follows:

1) Improvement of networking in the field of adrenal research in Europe through
integration of local and national research efforts
2) Implementation of an European adrenal tumour registry and associated biobank
3) Improvement of differential diagnosis and risk stratification of adrenal
tumours
4) Identification and validation of tools for follow-up of patients with
adrenal tumours
5) Identification of novel biomarkers for evaluating treatment response in
patients with adrenal tumours
6) Screening for molecular mechanisms as the basis to improve treatment
response in patients with adrenal tumours

- study design: European multi-central retrospective and prospective register
study and associated biobank.

- study duration: In a first step, patient enrolment and biomaterial collection
is planned for 10 years. However, in case of positive interim analysis this
timeframe will be extended. The registry will be maintained for at least 20
years.

- proposed number of patients: Participating European Centers will aim to enrol
as many patients with adrenal tumours as possible. An upper limit of patients
included in the registry is not defined.

The benefits of optimized grading, management and potentially better patient
treatment decisions based on biomarker results needs to be balanced against the
patient burden including providing clinical information, blood and urine
samples and surgical tissue specimens. This balance needs to be cognisant of
the ethical principles underlying such scientific research. Our belief is that
the benefits to the patient (at least in the long-term perspective) far
outweigh the burden imposed. Implementing standardized collections of tumour
samples and annotations is necessary to achieve the proposed scientific
objectives.