Faculty Bibliography

CONTEXT/BACKGROUND:The biochemical diagnosis of carcinoid syndrome (CS) is established through the measurement of 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA), but these measurements are prone to sampling error and may be troublesome for patients. Serum 5-HIAA measurements might constitute a more reliable and convenient alternative to diagnose CS. OBJECTIVE:To assess the diagnostic value of serum 5-HIAA measurements in patients with CS. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary care hospital. PATIENTS/METHODS:379 patients with a neuroendocrine tumor (NET), of whom 136 (35.9%) had CS, and 153 control samples were included. INTERVENTION/METHODS:Paired serum and 24-hour urine 5-HIAA measurements. MAIN OUTCOME MEASURE(S)/METHODS:Performances of serum and 24-hour urine 5-HIAA for the diagnosis of CS, measured by area under the receiver operating characteristics curve (AUROC). RESULTS:Serum 5-HIAA performance was similar to that of 24-hour urine 5-HIAA for the diagnosis of CS in the total NET cohort (n=379, AUROC 0.824 vs. 0.843, p=0.50) and in a subgroup of somatostatin analogue (SSA)-naïve patients (n=141, AUROC 0.915 vs. 0.938, p=0.66). Optimal cutoff value of serum 5-HIAA for the diagnosis of CS was 139.4 nmol/L (sensitivity 96.3%, specificity 87.6%) as determined in a subgroup analysis of SSA-naive patients with CS and controls. Serum 5-HIAA correlated well with 24-hour urine 5-HIAA (r=0.892, p<0.001) and the presence of flushing, diarrhea and carcinoid heart disease (OR 1.047-1.073 for every 100 nmol/L increase, p<0.001). CONCLUSIONS:Serum 5-HIAA measurements are equivalent to 24-hour urine 5-HIAA measurements for the diagnosis of CS in patients with NET and form an accessible alternative.

Non-mutational epigenetic reprogramming is considered an important enabling characteristic of neoplasia. Corticotroph tumors and other subtypes of pituitary tumors are characterized by distinct epigenetic profiles. The DNA methylation profile is consistent with disease-specific gene expression, which highlights the importance of epigenetic changes in tumor formation and progression. Elucidating the epigenetic changes underlying tumorigenesis plays an important role in understanding the molecular pathogenesis of corticotroph tumors and may ultimately contribute to improving tumor-specific treatment. Here, we provide an overview of the epigenetic landscape of corticotroph tumors. We also review the role of epigenetics in silencing the expression of tumor suppressor genes and promoting oncogenes expression, which could potentially be involved in the pathogenesis of corticotroph tumors. We briefly discuss microRNAs and epigenetic aspects of POMC regulation. Lastly, since the epigenetic changes are reversible, we discuss drugs that target epigenetic modifiers that could potentially be used in the arsenal of Cushing's disease treatment modalities.

The objective of this study was to establish recommendations for thromboprophylaxis in patients with endogenous Cushing's syndrome (CS), addressing the elevated risk of venous thromboembolism (VTE) associated with hypercortisolism. A Delphi method was used, consisting of 4 rounds of voting and subsequent discussions. The panel included 18 international experts from 11 countries and 4 continents. Consensus was defined as ≥75% agreement among participants. Recommendations were structured into the following categories: thromboprophylaxis, perioperative management, and VTE treatment. Consensus was reached on several critical areas, resulting in 14 recommendations. Key recommendations include: thromboprophylaxis should be considered at time of CS diagnosis and continued for 3 months after biochemical remission, provided there are no obvious contraindications. The standard weight-based prophylactic dose of low molecular-weight heparin is the preferred agent for thromboprophylaxis in patients with CS. Additionally, perioperatively and around inferior petrosal sinus sampling, thromboprophylaxis should be reconsidered if not already initiated at diagnosis. For VTE treatment, extended thromboprophylaxis is advised continuing for 3 months after Cushing is resolved. These Delphi consensus-based recommendations aim to standardize care practices and enhance patient outcomes in CS by providing guidance on thromboprophylaxis, including its initiation and continuation across various disease states, as well as the preferred agents to use. The panel also highlighted key areas for further research, particularly regarding the use of direct oral anticoagulants in CS and the management of mild CS and mild autonomous cortisol secretion. Additionally, the optimal duration of anticoagulant prophylaxis following curative treatment remains uncertain.

Up to 30% of adrenocortical carcinoma (ACC) patients have metastasised disease upon initial presentation, and systemic treatments currently fail to sufficiently improve survival. Palliative primary tumour resection can be considered for symptomatic relief, but its potential survival benefit remains a topic of debate. This systematic review therefore aims to assess the effect of primary tumour resection on overall survival in patients with metastatic ACC. A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant databases were searched from 2000 to 2024 for studies on primary tumour resection in metastatic ACC. Overall survival data were analysed. A total of 13 studies on primary tumour resection for metastatic ACC were included. All studies were retrospective and assessed as having a high risk of bias. Data regarding adequate patient characteristics and indications for surgery were missing in all studies. Hence, the current literature is hampered by both indication and selection biases to draw any conclusions on the survival benefit of primary tumour resection in patients with metastasised ACC. However, 12 out of 13 studies (92%) demonstrated longer overall survival after primary tumour resection compared to no surgery. Whereas this is in line with retrospective data on other cancers, randomised controlled trials in other tumours, such as breast and colorectal cancers, have failed to display survival benefits of primary tumour resection. These cancers are, however, relatively chemo-sensitive, unlike ACC. Primary tumour resection could therefore only be considered on an individual patient basis.

Adrenal masses are being found more and more often over the years. Given the association of these masses with advancing age, the decision to perform surgery in older, sometimes asymptomatic patients presents a clinical dilemma. These patients are potentially more vulnerable to adverse postoperative outcomes due to increased frailty. Therefore, this study aimed to compare the postoperative course after adrenalectomy in patients aged 70 years and older to that of a younger cohort. This single center retrospective study included patients aged ≥ 70 years who underwent adrenalectomy between 2000-2020, and propensity-score matched younger patients (< 70 years). Patients were matched based on hormonal overproduction, malignant diagnosis, surgical approach and year of surgery. The study included 77 elderly patients (median age 74 years) and 77 younger patients (median age 52 years; p < 0.001). Serious complications (Clavien-Dindo ≥ 3) occurred in 9.1% of elderly patients and 6.5% of the matched younger cohort (p = 0.773). The overall complication rate was 44.2% in elderly and 40.3% in younger patients (p = 0.771), with similar duration of hospital admission and mortality in both groups. Elderly patients experienced mostly infectious (33.8%) or cardiovascular complications (27.0%), and cardiovascular complications were more frequent in elderly than in younger patients (6.7%, p = 0.039). In conclusion, patients aged 70 years and older who undergo adrenalectomy have a similar postoperative course and complication rate as younger patients, with most postoperative complications being minor, and mortality being minimal. Therefore, older age itself should not be a reason to refrain from adrenalectomy.

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non-functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full-text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer-reviewed journal. The full-text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case-control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre-operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings.

The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Cushing's syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing's syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing's syndrome). An early diagnosis of Cushing's syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing's syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing's syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing's syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing's syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80-85%) or ACTH-independent (15-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of 'Approach to the patient' the diagnostic workup of Cushing's syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.

OBJECTIVE:Prolactin secreting tumors respond well to medical management with a small fraction of patients requiring surgery. We conducted a systematic review and meta-analysis to study the determinants of surgical remission in these tumors. METHODS:We searched PubMed to identify eligible studies reporting postoperative remission in patients treated with transsphenoidal surgery for prolactinoma. Primary outcomes included postoperative remission, follow-up remission, and recurrence. Postoperative and follow-up remission were defined as normoprolactinemia at less than and greater than one-year post-operation respectively. Recurrence was defined as hyperprolactinemia after initial normalization of prolactin levels. Odds ratios (OR) were calculated, stratified by radiological size, tumor extension, and tumor invasion, and analyzed using a random-effects model meta-analysis. RESULTS:Thirty-five studies were included. Macroadenomas were associated with lower rates of postoperative remission OR 0.20, 95% confidence interval [CI] 0.16-0.24) and lower rates of remission at follow-up (OR 0.11, 95% CI 0.053-0.22). Postoperative remission was less likely in tumors with extra- or suprasellar extension (OR 0.16, 95% CI 0.06-0.43) and tumors with cavernous sinus invasion (OR 0.03, 95% CI 0.01-0.13). Female gender and absence of preoperative dopamine agonist (DA) treatment were also associated with higher remission rates. Across the included studies, there was considerable heterogeneity in each primary outcome (postoperative remission I2=94%, follow-up remission I2=86%, recurrence I2=68%). CONCLUSIONS:Transsphenoidal surgery for prolactinomas may be particularly effective in small, non-invasive, treatment naive tumors and may provide a viable first-line alternative to dopamine agonist therapy in such patients.