Changes in nonfunctional adrenal incidentaloma after COVID-19 infection and a model for predicting benign and malignant adrenal incidentaloma.

Aims: To compare nonfunctional adrenal incidentalomas (NFAI) in individuals with and without a history of COVID-19 infection, while also establishing predictive models for distinguishing between benign and malignant adrenal incidentalomas (AI). Methods: A retrospective collection of data from patients with AI who underwent surgery and were verified in our hospital between April 2022 and June 2023 was conducted. A total of 121 patients were included in the study. Demographic information, tumor characteristics, functional indicators, and complications were compared among the patients. Statistical analyses utilized the t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables. Results: Patients with COVID-19 exhibited a higher prevalence of obesity (84.2% vs. 63.3%, P=0.048) and elevated direct bilirubin (DBIL) levels (44.1% vs. 19.2%, P=0.043) compared to those without COVID-19. Moreover, patients with Malignant AI, in contrast to Benign AI, showed higher normal total protein (TP) levels (28.8% vs. 57.1%, P=0.016) and larger tumor sizes (20 vs. 32.5mm, P=0.009). Univariate analysis identified low TP (OR=0.303, 95% CI=0.111-0.825, P=0.020) and tumor size (OR=1.045, 95% CI=1.011-1.080, P=0.009) as potential risk factors for multivariate analysis. A predictive model comprising clinical risk factors (tumor size and low TP) demonstrated an AUC of 0.754 (95% CI, 0.603-0.904) with a sensitivity of 0.75 and specificity of 0.775. The calibration curve revealed a bias-corrected AUC of 0.77. Conclusion: No discernible differences in the clinical manifestations of adrenal incidentalomas were observed between cases with and without a history of COVID-19 infection. However, AI with larger tumor diameters and lower than normal levels of total protein exhibited a more pronounced malignant potential.

Demographic and Clinical Characteristics of Patients with Adrenal Incidentaloma from a Single Center in South India: A Retrospective Study.

CONTEXT: Adrenal incidentalomas (AIs) are relatively uncommon neoplasms in 2% of apparently healthy individuals requiring evaluation for functionality and malignancy. AIM: We aimed to study the clinical, biochemical, and radiological profiles of patients presenting with AI and histopathological outcomes of those undergoing adrenalectomy. Materials and Methods: This retrospective study enrolled 62 AI patients attending a tertiary care center in South India between January 2016 and October 2023. Demographic details, radiological features, functionality, and histopathological data were analyzed. RESULTS: Out of 62 patients, total masses evaluated were 65 indicating bilaterality in 3 patients. The female: male ratio was 1.69, with a median age of 55 years (interquartile range: 44-64 years). 45.1% of individuals were >60 years. The most common indication for imaging was pain abdomen in 43 (69.4%). The median size was 3.2 cm. Fifty-five (88.7%) were assessed for functionality and 27 (49.1%) were functional. Among the 62 individuals, 14 (20.2%) had hypercortisolism, 11 (15.9%) had pheochromocytoma, 5 (7.24%) had primary hyperaldosteronism (PA), and 4 (5.7%) had hyperandrogenism including plurihormonal in 7. A mass size of 3.2 cm was of great value in distinguishing functional tumors with a sensitivity of 72% and specificity of 66% with an area under the curve of 0.682. A total of 34 (54.8%) patients underwent adrenalectomy. On histopathological examination, Adenoma (44.1%) was the most common followed pheochromocytoma (26.5%), adrenal cysts (8.8%), and Myelolipoma (5.9%). Two (5.9%) incidentalomas were adrenocortical carcinoma (ACC). Eight (53.3%) adenomas were functional with 6 having hypercortisolism (including 1 with hyperandrogenism) and 2 with PA. CONCLUSION: In our experience, the incidence of pheochromocytoma was second most common after adenoma. Since most functional tumors (60%) and all ACCs were ≥4 cm, a thorough biochemical evaluation for hormonal excess and evaluation for malignancy followed by surgery should be considered for lesions, especially ≥4 cm. Thus, we report the baseline demographic and clinical characteristics of patients with AI from a single center in South India.

Résumé Contexte:Les incidents surrénaliens (AIS) sont des néoplasmes relativement rares chez 2% des individus apparemment en bonne santé nécessitant une évaluation de la fonctionnalité et de la malignité. Objectif: Nous visions à étudier les profils cliniques, biochimiques et radiologiques des patients présentant IA et résultats histopathologiques de ceux qui subissent une surrénalectomie.Matériaux et méthodes:Cette étude rétrospective a inscrit 62 patients AI fréquentant un centre de soins tertiaires dans le sud de l'Inde entre janvier 2016 et octobre 2023. Les détails démographiques, les caractéristiques radiologiques, les fonctionnalités et les données histopathologiques ont été analysés.Résultats:Sur 62 patients, les masses totales évaluées étaient 65 indiquant la bilatéralité chez 3 patients. Le ratio féminin: mâle était de 1,69, avec un âge médian de 55 ans (intervalle interquartile: 44­64 ans). 45,1% des individus étaient> 60 ans. L'indication la plus courante pour l'imagerie était l'abdomen de la douleur dans 43 (69,4%). La taille médiane était de 3,2 cm. Cinquante-cinq (88,7%) ont été évaluées pour les fonctionnalités et 27 (49,1%) étaient fonctionnelles. Parmi les 62 individus, 14 (20,2%) avaient un hypercortisolisme, 11 (15,9%) Le phéochromocytome, 5 (7,24%) avait une hyperaldostéronisme primaire (PA), et 4 (5,7%) avaient l'hyperandrogénisme, y compris le plurihormonal dans 7. Une taille de masse de 3,2 cm était d'une grande valeur dans la distinction des tumeurs fonctionnelles avec une sensibilité de 72% et une spécificité distinctive de 66% avec une zone sous la courbe de 0,682. Au total, 34 (54,8%) patients ont subi une surrénalectomie. À l'examen histopathologique, l'adénome (44,1%) était le phéochromocytome suivi le plus courant (26,5%), les kystes surrénaliens (8,8%) et le myélolipome (5,9%). Deux incidentsalomes (5,9%) étaient un carcinome surrénocortical (ACC). Huit (53,3%) adénomes étaient fonctionnels avec 6 souffrant d'hypercortisolisme (dont 1 avec l'hyperandrogénisme) et 2 avec PA.Conclusion:D'après notre expérience, l'incidence du phéochromocytome était la deuxième plus courante après l'adénome. Étant donné que la plupart des tumeurs fonctionnelles (60%) et tous les ACC étaient ≥ 4 cm, une évaluation biochimique approfondie pour l'excès hormonal et l'évaluation de la malignité suivie d'une chirurgie doivent être envisagées pour les lésions, en particulier ≥4 cm. Ainsi, nous rapportons les caractéristiques démographiques et cliniques de base des patients atteints d'IA d'un seul centre du sud de l'Inde.

Clinical, radiological, and surgical outcomes of 431 patients with adrenal incidentalomas: retrospective study of a 10-year single-center experience.

Background/aim: The incidence of adrenal tumors is increasing due to the widespread utilization of radiographic imaging techniques. Factors such as tumor size, radiological characteristics, and functionality of adrenal adenomas play crucial roles in diagnosis and subsequent management. In this retrospective study, we investigated the clinical, radiological, and surgical features of patients with adrenal incidentalomas (AIs) and evaluated their follow-up results. Materials and methods: We analyzed data from 431 patients diagnosed with AIs (130 males, 301 females) who underwent adrenal hormone evaluation at our center. We compared nonfunctioning and functioning AIs in terms of radiological features. We also compared baseline and follow-up characteristics in nonfunctioning AIs. Results: The mean age of the patients was 55.4 ± 11.5 years, with a mean tumor size of 25.9 ± 14.3 mm. Mean follow-up duration was 3.17 ± 2.07 years. Adenoma localization revealed 165 (38.3%) right-sided, 185 (42.9%) left-sided, and 81 (18.8%) bilateral cases. Most patients (76.6%) had nonfunctioning AIs. During follow-up, nonfunctioning AIs exhibited increased fasting blood glucose, fasting insulin and HOMA-IR values (p = 0.002, <0.001 and 0.004, respectively). Among the functioning AIs cases (23.4%), autonomous cortisol secretion, Cushing's syndrome, pheochromocytoma, and primary aldosteronism were observed in 10.4%, 5.1%, 3.9%, and 3.9% of cases, respectively. Receiver operating characteristic curve analysis determined an adrenal adenoma size of 26.5 mm as the optimal cut-off for distinguishing between functioning and nonfunctioning AIs, with a sensitivity and specificity of 61.4% and 70.0%, respectively. Conclusion: Although the majority of AIs are nonfunctioning, the prevalence of functioning adrenal adenomas is not rare. Our findings suggest that adenoma size emerges as a valuable predictor for early detection of functioning adenomas. In addition, smaller masses appear to carry a lower risk of malignancy.

Hypertension and cardiac damage in pheochromocytoma and paraganglioma patients: a large-scale single-center cohort study.

BACKGROUND: Hypertension (HT) is one of the most common manifestations in patients with catecholamine-secreting neuroendocrine tumors. Although the cardiovascular manifestations of these tumors have been described, there have been no large-scale investigations of the profile of HT and changes in cardiac structure and function that occur in patients with pheochromocytomas and paragangliomas (PPGL). MATERIALS AND METHODS: In this study, we investigated the prevalence of HT and left ventricular remodeling (LVR) in a cohort of 598 patients who underwent surgery for PPGL at our center between January 2001 and April 2022. Information on demographics, reason for hospitalization, medical history, biochemical parameters, findings on echocardiography, and tumor characteristics were recorded. The LVR index was compared according to whether or not there was a history of HT. RESULTS: The average age was 47.07 ± 15.07 years, and 277 (46.32%) of the patients were male. A history of HT was found in 423 (70.74%) of the 598 patients. Paraganglioma was significantly more common in the group with HT (26.00% vs. 17.71%, P = 0.030) and significantly less likely to be found incidentally during a health check-up in this group (22.93% vs. 59.43%, P < 0.001). Among 365 patients with complete echocardiography data, left ventricular mass index (86.58 ± 26.70 vs. 75.80 ± 17.26, P < 0.001) and relative wall thickness (0.43 ± 0. 08 vs. 0.41 ± 0.06, P = 0.012) were significantly higher in patients with PPGL and a history of HT. The proportions with left ventricular hypertrophy (LVH) (19.40% vs. 8.25%, P = 0.011) and LVR (53.73% vs. 39.18%, P = 0.014) were also higher when there was a history of HT. After adjusting for age, gender, body mass index, alcohol consumption, smoking status, diabetes, stroke, creatinine level, tumor location, and tumor size, a history of HT was significantly correlated with LVH (odds ratio 2.71, 95% confidence interval 1.18-6.19; P = 0.018) and LVR (odds ratio 1.83, 95% confidence interval 1.11-3.03; P = 0.018). CONCLUSION: HT is common in patients with PPGL (70.74% in this cohort). PPGL without a history of HT is more likely to be found incidentally (59.43% in our cohort). HT is associated with LVR in PPGL patients with complete echocardiography data. These patients should be observed carefully for cardiac damage, especially those with a history of HT.

Are comorbidities of patients with adrenal incidentaloma tied to sex?

Background: A recent cross-sectional study showed that both comorbidities and mortality in patients with adrenal incidentaloma (AI) are tied to sex. However, few longitudinal studies evaluated the development of arterial hypertension, hyperglycemia, dyslipidemia and bone impairment in patients with AI. The aim of this study is to analyze the impact of sex in the development of these comorbidities during long-term follow-up. Methods: We retrospectively evaluated 189 patients (120 females, 69 males) with AI, from four referral centers in Italy and Croatia. Clinical characteristics, comorbidities and cortisol after 1-mg dexamethasone suppression test (1-mg DST) were assessed at baseline and at last follow-up visit (LFUV). Median follow-up was 52 (Interquartile Range 25-86) months. Results: The rates of arterial hypertension and hyperglycemia increased over time both in females (65.8% at baseline versus 77.8% at LFUV, p=0.002; 23.7% at baseline versus 39.6% at LFUV, p<0.001; respectively) and males (58.0% at baseline versus 69.1% at LFUV, p=0.035; 33.8% at baseline versus 54.0% at LFUV, p<0.001; respectively). Patients were stratified in two groups using 1.8 µg/dl as cut-off of cortisol following 1-mg DST: non-functional adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS). In the NFAT group (99 patients, females 62.6%), at baseline, we did not observe any difference in clinical characteristics and comorbidities between males and females. At LFUV, males showed a higher frequency of hyperglycemia than females (57.6% versus 33.9%, p=0.03). In the MACS group (89 patients, females 64.0%), at baseline, the prevalence of hypertension, hyperglycemia and dyslipidemia was similar between sexes, despite females were younger (60, IQR 55-69 versus 67.5, IQR 61-73, years; p=0.01). Moreover, females presented higher rates of bone impairment (89.3% versus 54.5%, p=0.02) than males. At LFUV, a similar sex-related pattern was observed. Conclusion: Patients with AI frequently develop arterial hypertension and hyperglycemia and should be periodically checked for these comorbidities, regardless of sex. In patients with MACS, the lack of difference between sexes in the frequency of cardiometabolic comorbidities despite that females are younger, and the higher frequency of bone impairment in females, suggest a sex-specific effect of cortisol.

Seventy years of pheochromocytomas and paragangliomas in Argentina. The FRENAR database.

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors characterized by the excessive production of catecholamines. This study aims to describe the clinical characteristics of PPGL cases in Argentina over recent decades. A multicenter retrospective cross-sectional analysis was carried out using a database comprising both pediatric and adult patients with confirmed PPGL diagnoses based on pathological reports. A cohort of 486 patients with PPGL was recruited. Women represent 58.4% of the patients, with a mean age of 38.3 years old at the time of diagnosis and 15.2% of the patients were under the age of 18. Hypertension, as well as classic signs and symptoms, were present in 80.9% of the patients. The adrenal incidentaloma, as a mode of presentation, increased in the last two decades rising from 3.9% (1953-2000) to 21.8% (2001-2022), p<0.001. Most tumors were located within the adrenal glands, accounting 83.0% of the cases, with bilateral occurrences noted in 20.0%. The median tumor size was 4.8cm. Local recurrence and metastases were observed in 10.9% and 12.2%. Out of 412 patients, 87.0% exhibited urinary excretion elevation of catecholamines and/or their metabolites. Furthermore, 148 patients, representing 30.4% of the study population, displayed a distinct genetic profile indicative of hereditary syndromes. The distribution of hereditary syndromes revealed that MEN2, VHL, and PGL4 constituted the most prevalent syndromes. This population-based study, spanning seven decades, offers valuable insights into the demographic and clinical characteristics of PPGL patients in Argentina.

Genetic predisposition to pheochromocytoma and paraganglioma: 21 years of experience in the field.

CONTEXT: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with high heritability, justifying systematic genetic screening for a germline variant in one of the twenty predisposing genes described to date. PURPOSE: To describe the experience of one endocrine oncogenetic laboratory over a period of 21 years (2001-2022), from the beginning of PPGL genotyping with Sanger sequencing in 2001 to the implementation of next-generation sequencing (NGS). METHOD: The activity database of an academic oncogenetic laboratory was searched to extract patients/relatives identified with a pathogenic variant/likely pathogenic variant (PV/LPV) over a period of 21 years. Clinical and genetic data were compared. RESULTS: In total, 606 index cases with PPGL and 444 relatives were genotyped. Genotyping of index cases was performed by Sanger sequencing and gene deletion analysis in 327 cases and by NGS in 279. Germline PV/LPV spanning 10 genes was identified in 165 index cases (27.2%). Several recurrent PV/LPVs in SDHx were observed in non-related index cases, the most frequent being SDHD, c.170-1G>T (n=28). This subgroup showed great phenotypic variability both between and within families in terms of both tumor location and number. Four patients (1.1%) with PV/LPV in SDHx had 3PA (Pituitary Adenoma and pheochromocytoma/paraganglioma) syndrome. 258 relatives (58.1%) had inherited a PV/LPV in one driver gene. The rate of PV/LPV carriers who were symptomatic at first imaging evaluation was 32%, but varied between<20% in SDHB and SDHC and >50% in SDHD, VHL and MAX. CONCLUSION: Our experience confirmed previously established genotype-phenotype correlations, but also highlights atypical clinical presentations, even for the same genetic variant. These data must be taken into account for optimal patient follow-up and management.

Adolescent- and adult-onset neuroblastic tumor: A retrospective multicenter observational study of patients diagnosed in France between 2000 and 2020.

BACKGROUND: Adult- and adolescent-onset neuroblastomas are rare, with no established therapy. In addition, rare pheochromocytomas may harbor neuroblastic components. This study was designed to collect epidemiological, diagnostic and therapeutic data in order to better define the characteristics of malignant peripheral neuroblastic tumors (MPNT) and composite pheochromocytomas (CP) with MPNT. PROCEDURE: Fifty-nine adults and adolescents (aged over 15 years) diagnosed with a peripheral or composite neuroblastic tumor, who were treated in one of 17 institutions between 2000 and 2020, were retrospectively studied. RESULTS: Eighteen patients with neuroblastoma (NB) or ganglioneuroblastoma (GNB) had locoregional disease, and 28 patients had metastatic stage 4 NB. Among the 13 patients with CP, 12 had locoregional disease. Fifty-eight percent of the population were adolescents and young adults under 24 years of age. The probability of 5-year event-free survival (EFS) was 40% (confidence interval: 27%-53%). CONCLUSIONS: Outcomes were better for patients with localized tumor than for patients with metastases. For patients with localized tumor, in terms of survival, surgical treatment was the best therapeutic option. Multimodal treatment with chemotherapy, surgery, radiotherapy, and immunotherapy-based maintenance allowed long-term survival for some patients. Adolescent- and adult-onset neuroblastoma appeared to have specific characteristics associated with poorer outcomes compared to pediatric neuroblastoma. Nevertheless, complete disease control improved survival. The presence of a neuroblastic component in pheochromocytoma should be considered when making therapeutic management decisions. The development of specific tools/resources (Tumor Referral Board, Registry, biology, and trials with new agents or strategies) may help to improve outcomes for patients.

Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

Adrenal tumors in patients with neuroendocrine neoplasms.

PURPOSE: To study the prevalence of primary adrenal tumors and adrenal metastases in patients with neuroendocrine neoplasms (NENs) and describe these in detail. NENs can be further divided into neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC). METHODS: A review of medical files was conducted for all patients who underwent a 68Gallium-DOTATOC-PET/CT during 2010-2023 or adrenalectomy during 1999-2023 at the Karolinska University Hospital. RESULTS: In total, 68Gallium-DOTATOC-PET/CT was performed on 1750 individuals with NEN, among whom 12 (0.69%) had adrenal tumors. Of these, 9 (0.51%) were NEN metastases. Out of 1072 adrenalectomies, 4 (0.37%) showed evidence of NEN metastases. Thus, 16 patients with NEN exhibited adrenal tumors. The adrenal tumors were found on average 5 years after the NEN diagnosis and 19% of the adrenal tumors with simultaneous NEN were benign. Few had all adrenal hormones measured. None had an adrenal insufficiency nor an adrenal biopsy. Another synchronous metastasis was found in 69% at the time of the adrenal tumor discovery. During the median 2-year follow-up, 38% of the subjects had deceased (with the exclusion of individuals presenting supposedly benign adrenal tumors 31%) all due to tumor complications. A comparison between individuals identified through 68Gallium-DOTATOC-PET/CT and those who underwent adrenalectomy revealed a higher prevalence of NETs in the former group and NECs in the latter group. CONCLUSION: Adrenal primary tumors and adrenal metastases are infrequent occurrences in patients with NEN. Most cases involved the presence of NEN metastasis upon the initial discovery of adrenal tumors. The overall prognosis was found to be favorable.