Diagnosis and management of secondary adrenal crisis.

Adrenal crisis (AC) is a life threatening acute adrenal insufficiency (AI) episode which can occur in patients with primary AI but also secondary AI (SAI), tertiary AI (TAI) and iatrogenic AI (IAI). In SAI, TAI and IAI, AC may develop when the HPA axis is unable to mount an adequate glucocorticoid response to severe stress due to pituitary or hypothalamic disruption. It manifests as an acute deterioration in multi-organ homeostasis that, if untreated, leads to shock and death. Despite the availability of effective preventive strategies, its prevalence is increasing in patients with SAI, TAI and IAI due to more frequent exogenous steroid administration, pituitary immune-related effects of immune checkpoint inhibitors and opioid use in pain management. The delayed diagnosis of acute AI which remains infrequently suspected increases the risk of AC. Its main precipitating factors are infections, emotional distress, surgery, cessation or reduction in GC doses, pituitary infarction or surgical cure of endogenous Cushing's syndrome. In patients not known previously to have SAI/TAI/IAI, recognition of its symptoms, signs, and biochemical abnormalities can be challenging and cause delay in proper diagnosis and therapy. Effective therapy of AC is rapid intravenous administration of hydrocortisone (initial bolus of 100 mg followed by 200 mg/24 h as continuous infusion or bolus of 50 mg every 6 h) and 0.9% saline. In diagnosed patients, preventive education in sick-day rules adjustment of glucocorticoid replacement and hydrocortisone parenteral self-administration must be performed repeatedly by trained health care providers. Strategies to improve the adequate preventive education in patients at risk for secondary AI should be promoted in collaboration with various medical specialist societies and patients support associations.

Sex-Related Differences in Self-Reported Symptoms at Diagnosis in Pheochromocytomas and Paragangliomas.

Context: Biological sex can play a role in the severity of certain diseases. Objective: Our objective was to evaluate whether sex-related differences affect the signs and symptoms of pheochromocytomas and paragangliomas (PPGLs) at presentation. Methods: We reviewed the records of patients with PPGLs at our center from 1995 to 2022. Results: Our study included 385 patients with PPGLs: 118 (30.6%) head and neck paragangliomas (HNPGLs), 58 (15.1%) thoracoabdominal paragangliomas (TAPGLs) and 209 (54.3%) pheochromocytomas (PHEOs). The cohort consisted of 234 (60.8%) women and 151 (39.2%) men. At diagnosis, more women than men presented with headaches (47.5% vs 32.4%; P = .007); however, more men presented with diabetes (21.1% vs 12.5%; P = .039). When subdivided by tumor location, headaches occurred more often in women with HNPGLs and TAPGLs (31.0% vs 11.4%; P = .0499 and 60.0% vs 21.7%; P = .0167). More men presented with diabetes among patients with PHEOs (28.2% vs 11.2%; P = .0038). In regard to nonsecretory PPGLs, women presented with a higher prevalence of headaches (46.9% vs 3.6%; P = .0002), diaphoresis (16.3% vs 0.0%; P = .0454), and palpitations (22.4% vs 0.0%; P = .0057). In patients with secretory tumors, women presented with more headaches (58.9% vs 42.7%; P = .0282) and men with more diabetes (29.3% vs 12.5%; P = .0035). Conclusion: In our cohort, more women presented with headaches across all tumor types and secretory statuses. More men presented with diabetes among patients with PHEOs and secretory tumors. In nonsecretory PPGLs, women had more adrenergic symptoms. These findings can be explained by differences in adrenergic receptor sensitivity, self-reported symptoms, and possibly other vasoactive peptides and sex-hormone status.

ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans.

BACKGROUND: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II). RESULTS: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination. CONCLUSIONS: Mutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.

BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.

Regional differences in stage distribution and rates of treatment for adrenocortical carcinoma across United States SEER registries.

BACKGROUND: We tested for regional differences across United States (US) in rates of adrenalectomy, systemic therapy, and adrenalectomy and systemic therapy combination for adrenocortical carcinoma (ACC) patients. We hypothesized that no differences exist, especially after accounting for baseline patient and tumor characteristics. METHODS: Within Surveillance, Epidemiology, and End Results (SEER) database (2004-2018), 1275 ACC patients were identified. Distribution of patient age, tumor size, ENSAT (European Network for the Study of Adrenal Tumors) stages, and treatments were tabulated and graphically displayed, according to nine geographical registries, corresponding to the population of specific states, cities or macro areas of the US on which the data are based on. Multinomial models predicted treatment probability for each patient according to registries. RESULTS: Patients count according to registries ranged from 62 to 509. Differences across registries existed for age (range 54-59 years; P=0.4), tumor size (8.5-11.0 cm; P=0.2), ENSAT stage (1-11% vs. 17-35% vs. 18-32% vs. 24-44%, in respectively ENSAT stage I, II, III, and IV), and treatment distribution (35-53% vs. 5-21% vs. 23-42%, in respectively adrenalectomy, systemic therapy, and adrenalectomy and systemic therapy combination; P=0.039). After adjustment for age, stage and year of diagnosis, clinically meaningful residual differences across registries remained for adrenalectomy (33-54%), systemic therapy (4-19%), and adrenalectomy and systemic therapy combination (20-38%). However, most variability originated from registries with smallest sample sizes. CONCLUSIONS: We identified important variability in ACC treatment according to SEER geographical registries, even after considering baseline patient and tumor characteristics. These findings may be indicative of differences in quality of care or expertise in ACC management.

Role of Adrenal Vein Sampling in Guiding Surgical Decision in Primary Aldosteronism.

Adrenal vein sampling (AVS) is recommended for subtyping primary aldosteronism (PA) to identify lateralized or bilateral sources of aldosterone excess, allowing for better decision-making in regard to medical or surgical management on a case-by-case basis. To date, no consensus exists on protocols to be used during AVS, especially concerning sampling techniques, the timing of sampling, and whether or not to use adrenocorticotropic hormone (ACTH) stimulation. Interpretation criteria for selectivity, lateralization, and contralateral suppression vary from one expert center to another, with some favoring strict cut-offs to others being more permissive. Clinical and biochemical post-operative outcomes can also be influenced by AVS criteria utilized to indicate surgical therapy.In this review, we reanalyze studies on AVS highlighting the recent pathological findings of frequent micronodular hyperplasia adjacent to a dominant aldosteronoma (APA) overlapping with bilateral idiopathic hyperaldosteronism (IHA) etiologies, as opposed to the less frequent unilateral single aldosteronoma. The variable expression of melanocortin type 2 receptors in the nodules and hyperplasia may explain the frequent discordance in lateralization ratios between unstimulated and ACTH- stimulated samples. We conclude that aldosterone values collected during simultaneous bilateral sampling, both at baseline and post-ACTH stimulation, are required to adequately evaluate selectivity, lateralization, and contralateral suppression during AVS, to better identify all patients with PA that can benefit from a surgical indication. Recommended cut-offs for each ratio are also presented.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

African American vs Caucasian race/ethnicity in adrenocortical carcinoma patients.

In some primaries, African American race/ethnicity predisposes to higher stage and worse survival. We tested for differences in cancer-specific mortality (CSM) and other-cause mortality (OCM) in patients with adrenocortical carcinoma (ACC) according to African American vs Caucasian race/ethnicity. We hypothesized that African Americans present with higher tumor stage and grade, do not receive the same treatment, and experience worse oncological outcomes than Caucasians. Within Surveillance, Epidemiology, and End Results database, we identified 1016 ACC patients: 123 (12.1%) African Americans vs 893 (87.9%) Caucasians. Propensity score matching (PSM) (age, sex, marital status, grade, T, N, and M stages, and treatment type), Poisson-smoothed cumulative incidence plots, and competing risk regression (CRR) were used. Compared to Caucasians, African Americans were more frequently unmarried (56.9% vs 35.5%, P < 0.001). No clinically meaningful or statistically significant differences were observed for age, grade, T, N, and M stages, as well as treatment type (all P > 0.05). After PSM (1:4), 123 African Americans and 492 Caucasians remained and were included in CRR analysis. In multivariable CRR models, CSM and OCM rates were not different between the two race/ethnicities (hazard ratio: 0.84, P = 0.3). In African Americans, 5-year CSM rates were 31.2% and 75.3% in European Network for the Study of Adrenal Tumors (ENSAT) stages I-II and III-IV, respectively vs 32.9% and 75.4% in Caucasians. Overall 5-year OCM rates were 11.0% vs 10.1% in respectively African Americans and Caucasians. Unlike other primaries, in ACC, African American race/ethnicity is not associated with higher disease stage at initial diagnosis or worse survival.

Central Hypothyroidism is Frequent During Mitotane Therapy in Adrenocortical Cancer Patients: Prevalence and Timeline.

CONTEXT: Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited. OBJECTIVE: To better characterize thyroid hormone insufficiency in patients exposed to mitotane. METHODS: We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment. RESULTS: In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: <3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation. CONCLUSION: Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.

Endogenous Cushing's syndrome during pregnancy.

Endogenous Cushing's syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism.

Clinical, Pathophysiologic, Genetic, and Therapeutic Progress in Primary Bilateral Macronodular Adrenal Hyperplasia.

Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein-coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.

Contemporary conditional cancer-specific survival rates in surgically treated adrenocortical carcinoma patients: A stage-specific analysis.

BACKGROUND AND OBJECTIVES: We examined the effect of disease-free interval (DFI) duration on cancer-specific mortality (CSM)-free survival, otherwise known as the effect of conditional survival, in surgically treated adrenocortical carcinoma (ACC) patients. METHODS: Within the Surveillance, Epidemiology, and End Results database (2004-2018), 867 ACC patients treated with adrenalectomy were identified. Conditional survival estimates at 5-years were assessed based on DFI duration and according to stage at presentation. Separate Cox regression models were fitted at baseline and according to DFI. RESULTS: Overall, 406 (47%), 285 (33%), and 176 (20%) patients were stage I-II, III and IV, respectively. In conditional survival analysis, providing a DFI of 24 months, 5-year CSM-free survival at initial diagnosis increased from 66% to 80% in stage I-II, from 35% to 66% in stage III, and from 14% to 36% in stage IV. In multivariable Cox regression models, stage III (hazard ratio [HR]: 2.38; p < 0.001) and IV (HR: 4.67; p < 0.001) independently predicted higher CSM, relative to stage I-II. The magnitude of this effect decreased over time, providing increasing DFI duration. CONCLUSIONS: In surgically treated ACC, survival probabilities increase with longer DFI duration. This improvement is more pronounced in stage III, followed by stages IV and I-II patients, in that order. Survival estimates accounting for DFI may prove valuable in patients counseling.

University of Montreal's Clinician-Investigator Program: A 10-Year Descriptive Evaluation.

PURPOSE: Clinician-investigators have an important role in the development and implantation of new therapies and treatment modalities; however, there have been several reports highlighting a pending shortage in the clinician-investigators' workforce. In Canada, the Royal College has promoted the development of clinician-investigators programs (CIP) to facilitate the training of these individuals. There is currently a paucity of data regarding the outcomes of such programs. This study aims to identify the strengths and areas of improvement of the Montreal University CIP.  Methods: An internet-based 51-question survey was distributed to all the alumni from the University of Montreal CIP. Participation was voluntary and no incentives were provided. The response rate was 64%.  Results: Among respondents, 50% (n=16) had completed their clinical residency and all CIP requirements. The majority of these individuals (63%) had become independent investigators and had secured provincial and national funding. Satisfaction of the respondents was high regarding the overall program (85%), the research skills developed during the CIP (84%) and the financial support obtained during the program (72%). The satisfaction rate regarding career planning was lower (63%).  Conclusion: This survey demonstrates that, while indicators are favorable, some areas still require improvement. Several steps to improve the CIP have been identified; notably, the transition from the CIP to early independent career has been identified as critical in the development of clinician-investigators and steps have been taken to improve this progression.

Hispanic vs. Caucasian Race/Ethnicity in Adrenocortical Carcinoma Patients.

BACKGROUND/AIM: In primaries other than adrenocortical carcinoma (ACC), Hispanic race/ethnicity may predispose to higher stage at initial diagnosis and may result in worse survival. We tested the association between Hispanic race/ethnicity and cancer specific mortality (CSM) in ACC patients in addition to testing for differences in other-cause mortality (OCM) rates between Hispanics and Caucasians. PATIENTS AND METHODS: Within Surveillance, Epidemiology, and End Results database (2004-2018), we identified 1,060 ACC patients: 167 (15.8%) Hispanics vs. 893 (84.2%) Caucasians. Propensity score matching (age, sex, grade, T, N and M stages, treatment types), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. RESULTS: Compared to Caucasians, Hispanics were younger (51 vs. 57 years, p<0.001) and presented higher rates of T3-4 primary tumor stage (52.7% vs. 42.8%, p=0.007). No other statistically significant differences were observed for grade, lymph node invasion, distant metastases, European Network for the Study of Adrenal Tumors (ENSAT) stage and treatment type (p>0.05 in all cases). After matching (1:3), 167 Hispanics and 501 Caucasians remained and were included in CRR analyses. In Hispanics, five-year CSM rates were 38.0% and 78.8% in respectively ENSAT stages I-II and III-IV vs. 34.1% and 74.4% in Caucasians. Overall, five-year OCM rates were 10.7% vs. 9.0% in Hispanics and Caucasians, respectively. In multivariable CRR models, Hispanic race/ethnicity was not an independent predictor for higher CSM (hazard ratio=1.18, p=0.2). CONCLUSION: In ACC, relative to Caucasians, Hispanic race/ethnicity is associated with lower age at initial diagnosis, but not with higher tumor stage or survival disadvantage.

Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma.

BACKGROUND: Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. CASE: A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. GENETIC ANALYSIS: After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. CONCLUSION: To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

Successful Adrenal Vein Sampling Using Dexamethasone Premedication in Patients With Iodine Contrast Media Allergy.

Context: Preparation of patients with iodine contrast media (ICM) allergy who require adrenal vein sampling (AVS) to establish source of aldosterone excess of their confirmed primary aldosteronism (PA) is controversial. Usual premedication with high-dose prednisone can interfere with cortisol determinations, possibly altering the aldosterone to cortisol ratios for the identification of lateralized aldosterone excess. Objective: We aimed to evaluate the efficacy and safety of premedication with high-dose dexamethasone to perform AVS in patients with ICM. Methods: One hundred and seventy-seven consecutive patients with confirmed PA who underwent bilateral simultaneous basal and post-ACTH bolus AVS at our center between January 2010 and December 2020 were retrospectively analyzed for history of ICM allergy. A total of 7 patients (4%) with previous allergic reactions to ICM were prepared with 3 doses of 7.5 mg dexamethasone premedication rather than the usual 50 mg of prednisone. Results: No breakthrough allergic reactions were reported in the 7 patients. Despite adequate serum cortisol suppression following dexamethasone, the basal and post-ACTH selectivity index were respectively > 2 and > 5 bilaterally in all patients, confirming adequate cannulation of both adrenal veins. Four patients had lateralized ratios (A/C ratio > 2 basally and > 4 post-ACTH), while 3 had bilateral source during AVS study. In the 3 patients undergoing unilateral adrenalectomy for lateralized source and contralateral suppression and adequate follow-up data, cure of PA was achieved at mean 58 months postoperatively. Conclusion: AVS using dexamethasone premedication is safe and accurate for diagnosing the source of aldosterone excess in patients with PA and ICM allergy.

Postoperative Recurrences in Patients Operated for Pheochromocytomas and Paragangliomas: New Data Supporting Lifelong Surveillance.

At least 10% of pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) may recur after the initial surgery. Guidelines recommend annual screening for recurrence in non-metastatic tumors for at least 10 years after the initial surgical resection and lifelong screening in high-risk patients. However, recent data suggest that a shorter follow-up might be appropriate. We performed a retrospective analysis on patients with PPGLs who had local and/or metastatic recurrences between 1995 and 2020 in our center. Data were available for 39 cases of recurrence (69.2% female) including 20 PHEOs (51.3%) and 19 PGLs (48.7%) (13 head and neck (HNPGL) and 6 thoracoabdominal (TAPGL)). The overall average delay of recurrence was 116.6 months (14-584 months) or 9.7 years and the median was 71 months or 5.9 years. One-third of the cohort had a recurrence more than 10 years after the initial surgery (10-48.7 years). The average tumor size at initial diagnosis was 8.2 cm for PHEOs, 2.7 cm for HNPGLs, and 9.6 cm for TAPGLs. Interestingly, 17.6% of PHEOs were under 5 cm at the initial diagnosis. Metastatic recurrence was identified in 75% of PHEOs, 15.4% of HNPGLs, and 66.7% of TAPGLs. Finally, 12/23 (52.2%) patients with recurrence who underwent genetic testing carried a germline mutation. Overall, the safest option remains a lifelong follow-up.

ARMC5 is part of an RPB1-specific ubiquitin ligase implicated in adrenal hyperplasia.

ARMC5 is implicated in several pathological conditions, but its function remains unknown. We have previously identified CUL3 and RPB1 (the largest subunit of RNA polymerase II (Pol II) as potential ARMC5-interacting proteins. Here, we show that ARMC5, CUL3 and RBX1 form an active E3 ligase complex specific for RPB1. ARMC5, CUL3, and RBX1 formed an active E3 specific for RPB1. Armc5 deletion caused a significant reduction in RPB1 ubiquitination and an increase in an accumulation of RPB1, and hence an enlarged Pol II pool in normal tissues and organs. The compromised RPB1 degradation did not cause generalized Pol II stalling nor depressed transcription in the adrenal glands but did result in dysregulation of a subset of genes, with most upregulated. We found RPB1 to be highly expressed in the adrenal nodules from patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) harboring germline ARMC5 mutations. Mutant ARMC5 had altered binding with RPB1. In summary, we discovered that wildtype ARMC5 was part of a novel RPB1-specific E3. ARMC5 mutations resulted in an enlarged Pol II pool, which dysregulated a subset of effector genes. Such an enlarged Pol II pool and gene dysregulation was correlated to adrenal hyperplasia in humans and KO mice.

Characterization of hyperlipidemia secondary to mitotane in adrenocortical carcinoma.

Background: This study examined the magnitude of changes and the time required to observe maximal changes in LDL-c, HDL-c, triglycerides (Tg) and non-HDL-c after the introduction of mitotane. Methods: Retrospective study of 45 patients with adrenocortical carcinoma who were treated at the Centre hospitalier de l'Université de Montréal. Clinical and biochemical data were collected, including lipid profiles before and during the first year of treatment with mitotane. Results: Among the 45 studied patients, 26 (58%) had a complete lipid profile before the introduction of mitotane and at least 1 lipid profile during the first year of treatment, and 19 patients (42%) had a lipid profile following initiation of the treatment. Among the 26 patients who had lipid profiles before and after the introduction of mitotane, the increase of LDL-c was 2.19 mmol/L (76%) (P< 0.0001), HDL-c was 0.54 mmol/L (35%) (P= 0.0002), Tg was 1.80 mmol/L (129%) (P< 0.0001) and non-HDL-c was 2.73 mmol/L (79%) (P< 0.0001). Between the first and the sixth month of mitotane treatment, peak values (n = 45) of LDL-c and non-HDL-c were reached in 42 patients (93%) and 37 patients (82%), respectively, whereas peak values of HDL-c were reached after 6 months of mitotane treatment in 29 patients (66%). The peak value of Tg was almost equal throughout the first year. The mean peak values of HDL-c, Tg and non-HDL-c showed significant associations with their respective mitotane concentrations (ß = 0.352, P= 0.03; ß = 0.406, P= 0.02 and ß = 0.339, P= 0.05). Conclusion: The introduction of mitotane produces a clinically significant elevation of lipid parameters (LDL-c, HDL-c, Tg and non-HDL-c) during the first year of treatment.