The mechanisms regulating cortisol production when ACTH of pituitary origin is suppressed in primary adrenal causes of Cushing's syndrome (CS) include diverse genetic and molecular mechanisms. These can lead either to constitutive activation of the cAMP system and steroidogenesis or to its regulation exerted by the aberrant adrenal expression of several hormone receptors, particularly G-protein coupled hormone receptors (GPCR) and their ligands. Screening for aberrant expression of GPCR in bilateral macronodular adrenal hyperplasia (BMAH) and unilateral adrenal tumors of patients with overt or subclinical CS demonstrates the frequent co-expression of several receptors. Aberrant hormone receptors can also exert their activity by regulating the paracrine secretion of ACTH or other ligands for those receptors in BMAH or unilateral tumors. The aberrant expression of hormone receptors is not limited to adrenal CS but can be implicated in other endocrine tumors including primary aldosteronism and Cushing's disease. Targeted therapies to block the aberrant receptors or their ligands could become useful in the future.
Nada El Ghorayeb, Isabelle Bourdeau, and André Lacroix
Isabelle Bourdeau, Nada El Ghorayeb, Nadia Gagnon, and André Lacroix
The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing’s disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.
Sofia S Pereira, Mariana P Monteiro, Isabelle Bourdeau, André Lacroix, and Duarte Pignatelli
Adrenocortical carcinomas (ACCs) are rather rare endocrine tumors that often have a poor prognosis. The reduced survival rate associated with these tumors is due to their aggressive biological behavior, combined with the scarcity of effective treatment options that are currently available. The recent identification of the genomic alterations present in ACC have provided further molecular mechanisms to develop consistent strategies for the diagnosis, prevention of progression and treatment of advanced ACCs. Taken together, molecular and genomic advances could be leading the way to develop personalized medicine in ACCs similarly to similar developments in lung or breast cancers. In this review, we focused our attention to systematically compile and summarize the alterations in the cell cycle regulation that were described so far in ACC as they are known to play a crucial role in cell differentiation and growth. We have divided the analysis according to the major transition phases of the cell cycle, G1 to S and G2 to M. We have analyzed the most extensively studied checkpoints: the p53/Rb1 pathway, CDC2/cyclin B and topoisomerases (TOPs). We reached the conclusion that the most important alterations having a potential application in clinical practice are the ones related to p53/Rb1 and TOP 2. We also present a brief description of on-going clinical trials based on molecular alterations in ACC. The drugs have targeted the insulin-like growth factor receptor 1, TOP 2, polo-like kinase1, cyclin-dependent kinase inhibitors, p53 reactivation and CDC25.
Isabelle Bourdeau, Sylvie Oble, Fabien Magne, Isabelle Lévesque, Katia Y Cáceres-Gorriti, Serge Nolet, Philip Awadalla, Johanne Tremblay, Pavel Hamet, Maria Candida Barisson Villares Fragoso, and André Lacroix
Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet.
We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out.
Morning ambulating cortisol post 1 mg DST were >50 nmol/l in 5/8 members in generation II (57–68 years old), 9/22 in generation III (26–46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. β-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of β-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests.
Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant β-adrenergic and V1-vasopressin receptors identified in this family remains to be elucidated.
Marie-Josée Desrochers, Matthieu St-Jean, Nada El Ghorayeb, Isabelle Bourdeau, Benny So, Éric Therasse, Gregory Kline, and André Lacroix
Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes.
To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure.
In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria.
Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure.
In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.
Mohamed-Karji Almarzooqi, Miguel Chagnon, Gilles Soulez, Marie-France Giroux, Patrick Gilbert, Vincent L Oliva, Pierre Perreault, Louis Bouchard, Isabelle Bourdeau, André Lacroix, and Eric Therasse
Many investigators believe that basal adrenal venous sampling (AVS) should be done simultaneously, whereas others opt for sequential AVS for simplicity and reduced cost. This study aimed to evaluate the concordance of sequential and simultaneous AVS methods.
Design and methods
Between 1989 and 2015, bilateral simultaneous sets of basal AVS were obtained twice within 5 min, in 188 consecutive patients (59 women and 129 men; mean age: 53.4 years). Selectivity was defined by adrenal-to-peripheral cortisol ratio ≥2, and lateralization was defined as an adrenal aldosterone-to-cortisol ratio ≥2, the contralateral side. Sequential AVS was simulated using right sampling at −5 min (t = −5) and left sampling at 0 min (t = 0).
There was no significant difference in mean selectivity ratio (P = 0.12 and P = 0.42 for the right and left sides respectively) and in mean lateralization ratio (P = 0.93) between t = −5 and t = 0. Kappa for selectivity between 2 simultaneous AVS was 0.71 (95% CI: 0.60–0.82), whereas it was 0.84 (95% CI: 0.76–0.92) and 0.85 (95% CI: 0.77–0.93) between sequential and simultaneous AVS at respectively −5 min and at 0 min. Kappa for lateralization between 2 simultaneous AVS was 0.84 (95% CI: 0.75–0.93), whereas it was 0.86 (95% CI: 0.78–0.94) and 0.80 (95% CI: 0.71–0.90) between sequential AVS and simultaneous AVS at respectively −5 min at 0 min.
Concordance between simultaneous and sequential AVS was not different than that between 2 repeated simultaneous AVS in the same patient. Therefore, a better diagnostic performance is not a good argument to select the AVS method.
Maria Candida B V Fragoso, Madson Queiroz Almeida, Tania L Mazzuco, Beatriz M P Mariani, Luciana P Brito, Talita Cardoso Gonçalves, Guilherme A Alencar, Lorena de O Lima, Andre M Faria, Isabelle Bourdeau, Antonio M Lucon, Daniel S Freire, Ana Claudia Latronico, Berenice B Mendonca, Andre Lacroix, and Antonio M Lerario
A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts.
To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients.
Patients and methods
BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients – 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT).
DLGAP5–PINK1 and BUB1B–PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival.
This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.