Molecular landscape and biomarker discovery in adrenocortical carcinoma: An integrative review of bioinformatics and translational insights.

Li-Fraumeni Syndrome (LFS) is an autosomal dominant condition associated with germline pathogenic variants in the tumor suppressor gene TP53. Carriers have a higher risk of developing multiple primary tumors and a broad spectrum of cancers. The main tumors include premenopausal breast cancer, sarcomas, adrenocortical carcinoma and central nervous system tumors. Melanoma is a recognized but uncommon manifestation of LFS, with few reports in the literature linking the syndrome to this malignancy. The main objective of this study is to evaluate the occurrence of melanoma in patients carrying the germline pathogenic variant in the TP53 gene, registered in the Brazilian Li-Fraumeni Syndrome Study (BLISS) database from 2018 to 2023. From our database, six out of 512 patients developed melanoma, with melanoma representing the sole clinical manifestation of LFS in half of these patients. Of the 512 patients with LFS, 417 were carriers of the R337H variant, and among them, three patients developed melanoma. Three melanomas were detected during routine surveillance with total-body photography and digital dermoscopy. This study shows that melanoma is one of the manifestations of LFS, highlighting the importance of its screening within the Toronto protocol. It is essential for healthcare professionals who manage patients with LFS to recognize this risk in order to enable early diagnosis and identification of precursor lesions.

Introduction: Oncocytic adrenocortical carcinoma (OAC) is a rare histologic variant of adrenocortical carcinoma. It is characterized by cells with abundant eosinophilic cytoplasm because of high mitochondrial content. Unlike conventional Adrenocortical carcinoma (ACC), which is typically aggressive, OAC often presents with a more indolent biological behavior. The paradoxical features of OAC make the diagnosis and management challenging. Case Report: A 45-year-old female presented with weight loss and left-sided abdominal pain, with initial imaging revealing a large (24 cm) left adrenal mass. Imaging revealed that the mass had radiologic signs and necrotic features concerning for malignancy. She subsequently underwent a left adrenalectomy with en bloc pancreatectomy, splenectomy, and left nephrectomy along with paraaortic lymphadenectomy. Histopathology revealed classic oncocytic morphology with low Ki-67 index (2%) and absence of any lymph node involvement, despite venous and capsular invasion. Due to the venous invasion alone, the tumor met the Lin–Weiss–Bisceglia (LWB) criteria for malignancy. Additional molecular analysis revealed a favorable diagnosis by showing TP53 alterations, low tumor burden, along with microsatellite stability. Postoperatively, the patient recovered and was administered external beam radiation. Conclusion: This case is an example of a rare subtype of ACC and highlights a clinical paradox. In patients with OAC, a large tumor size with necrosis may not always be associated with a poor prognosis. Additionally, OAC has unique diagnostic and management challenges due to its rare nature. However, surgery is still the mainstay treatment for OAC, with the role of mitotane in adjuvant therapy still being explored.

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with limited treatment options, commonly managed with mitotane, which can cause serious side effects, including central hypothyroidism and dyslipidemia. This study aimed to evaluate the incidence, clinical features, and relationship between mitotane-induced central hypothyroidism and dyslipidemia in ACC patients, as well as to investigate mitotane's direct toxic effects on thyroid cells. Thirty-eight ACC patients treated with mitotane for at least six months were monitored for thyroid function and lipid profiles. Central hypothyroidism developed in 50% of patients with normal baseline thyroid function, mostly women, who were at higher risk. Dyslipidemia occurred in 40% of patients, more frequently in men, and appeared earlier than hypothyroidism. In vitro experiments on rat thyroid cells demonstrated a dose-dependent toxic effect of mitotane on cell viability. No significant link was found between hypothyroidism and dyslipidemia risk. These findings reveal sex-specific susceptibilities to mitotane toxicity and provide novel evidence of direct mitotane-induced thyroid cell damage. This insight supports the need for careful thyroid and lipid profile monitoring during mitotane treatment and may inform the development of safer therapies for ACC.

We identified a germline TP53 c.758C > T (p.T253I) mutation in the TP53 tumor suppressor gene in a pediatric adrenocortical carcinoma (ACC) patient. Characteristic of pathogenic p53 mutations, we observed upregulation of total p53 protein levels in the patient’s ACC and concurrent suppression of the wild-type (WT) TP53 allele. As ACC can be associated with Li-Fraumeni Syndrome (LFS) and the mutation has not yet been linked to LFS, we sought to characterize the functionality of the T253I mutation. We acquired p53-/- HEK293 cells and stably transduced them with GFP-tagged wild type (T253) or T253I p53 as well as two established pathogenic p53 mutants (C176Y and R213X). Compared to p53 WT, levels of T253I p53 increased while MDM2 levels decreased, suggesting a loss of MDM2-mediated regulation of T253I p53. Additionally, T253I showed a reduction in DNA damage responsive events, diminished DNA binding capabilities, and blunted transactivation capacity. These experimental data lead us to conclude that T253I represents a pathologic variant in TP53 that may predispose to LFS-associated tumors.

The field of adrenal surgery encompasses a wide range of diseases, including various disorders of the adrenal cortex and medulla. This article reviews the latest advances in the diagnosis and treatment of major adrenal cortical diseases, such as primary aldosteronism, hypercortisolism, and adrenocortical carcinoma. The content mainly covers the updated pathological classification, optimized clinical guidelines, innovative diagnostic technologies, adjusted surgical strategies, and expanded non-surgical treatment methods for these major adrenal cortical diseases. It also involves research on disease pathogenesis and exploration of new therapeutic approaches. The purpose is to provide references for clinical diagnosis and treatment, promote the precise management of adrenal cortical diseases, and facilitate multidisciplinary collaboration to improve patient prognosis.

Synchronous embryonal rhabdomyosarcoma and adrenocortical carcinoma in a toddler with germline CBL pathogenic variant: A case report

Local control strategies in pediatric oncology are guided by disease-specific considerations. Effective communication of the goals of surgical procedure and associated intraoperative events plays a crucial role in shaping subsequent treatment decisions. However, accurately and comprehensively documenting these findings remains challenging, with considerable variability across different tumor types. This investigation aims to achieve a consensus on critical intraoperative oncologic observations pertaining to pediatric solid tumors, thereby facilitating the enhancement of surgical reporting and the optimization of subsequent treatment strategies. An expert panel comprising childhood cancer specialists from diverse disciplines and geographical regions participated in a Delphi consensus process. After reviewing relevant literature and engaging in multiple voting rounds, the panel identified essential tumor-specific intraoperative documentation elements. A Delphi panel of 16 experts from diverse geographical locations completed two rounds of voting with a 94% participant retention rate and achieved consensus on 15 key statements. Essential documentation components included completeness of resection, evaluation of locoregional spread, and vascular involvement, with tumor-specific variations. For instance, neuroblastoma required documentation of resection percentage, while sarcoma emphasized biopsy tract resection and plane of resection. Ovarian germ cell tumors necessitated ascitic fluid sampling and contralateral ovary evaluation. Additionally, the presence of tumor thrombus was highlighted as particularly relevant in renal, liver, and adrenocortical carcinomas. Despite recognizing the significance of these findings, the panel noted deficiencies in operative reports, including omissions of documentation of tumor spillage, lymph node sampling, and residual disease, underscoring the need for improved documentation to support multidisciplinary decision-making. This study highlights the critical role of precise intraoperative documentation in guiding multidisciplinary care for pediatric solid tumors. The variability across tumor types underscores the need for tailored documentation guidelines. While a standardized synoptic operative report could improve consistency and communication, a hybrid model combining universal elements with tumor-specific details may offer an effective solution for comprehensive and adaptable reporting.

Myxoid adrenocortical adenoma with pseudoglandular pattern: A clinicopathological study of a rare histologic variant and its diagnostic challenges.

miR-507 and miR-665 as central MicroRNA regulators in the ceRNA network of adrenocortical carcinoma: A systems biology approach

Investigating the role of posterior retroperitoneoscopic adrenalectomy (PRA) for the treatment of adrenocortical cancer (ACC). Between January 2010 and December 2024, 28 patients (9 men, 19 female) with am mean age of 51.5 ± 19.5 years (range: 1.6-82.3) underwent PRA for primary ACC. Tumor sizes ranged between 3 and 15cm (mean: 7.3cm). Hormonal hypersecretion was found in 12 patients. Surgeries were performed in a standardized 3-port technique in prone position. Follow-up (mean: 37.9 months) data could be obtained for 26 patients. There were 12 right and 16 left adrenalectomies. The mean operating time was 159.2 ± 100.9min (range: 35-340min). Seven conversions occurred (25%): five to an open approach and two to a laparoscopic approach. One patient with Cushing's syndrome died because of multiple organ failure in the postoperative period (4%). The mean follow-up time was 38.8 ± 35.3 months. Patients with stage I disease demonstrated a 5-year overall survival rate of 100%, whereas patients with stage II and III disease had 3-years survival rates of 64% and 50%, respectively. The posterior retroperitoneoscopic approach appears feasible in patient with confirmed or suspected ACC and can be proposed in selected cases.

Glyoxalase 1 (GLO1), an enzyme responsible for breaking down methylglyoxal (MG), is increasingly recognized as a tumor-promoting factor due to its role in removing cytotoxic MG. This study aims to analyze the expression status and prognostic significance of GLO1 across various cancers and explore its potential role in cancer immunotherapy. We obtained GLO1 mRNA expression profiles from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier analysis was used to evaluate the prognostic value of GLO1 in multiple cancers. We validated GLO1 protein expression in clinical endometrial cancer samples using immunohistochemical staining. Additionally, we analyzed GLO1's correlation with drug sensitivity from the Genomics of Drug Sensitivity in Cancer (GDSC) database and its relationship with the tumor microenvironment and immunotherapy response. GLO1 was widely expressed in human tumor tissues with significant differences compared to adjacent normal tissues. High GLO1 expression was associated with poor prognosis in 14 cancers, including adrenocortical carcinoma, cholangiocarcinoma, and lymphoid neoplasm diffuse large B-cell lymphoma. GLO1 expression was negatively related to immune cell infiltration in breast invasive carcinoma. In melanoma and kidney renal clear cell carcinoma, high GLO1 expression was linked to poor immunotherapy outcomes. This comprehensive pan-cancer study reveals the prognostic value and potential predictive role of GLO1 in immunotherapy across multiple tumor types. This study primarily utilized bioinformatic datasets; experimental validation was performed for endometrial cancer but warrants expansion to other cancer types in future work.

Adipose tissue (AT) closely interacts with the adrenal glands to regulate metabolism, energy balance, and stress responses. While the adrenal cortex secretes glucocorticoids and mineralocorticoids that influence AT distribution, lipid storage, and browning, the adrenal medulla releases catecholamines that acutely activate thermogenesis in brown and beige adipocytes. Under physiological conditions, this bidirectional crosstalk maintains energy homeostasis and cardiovascular stability. However, in adrenal diseases such as Cushing syndrome, primary aldosteronism, adrenocortical carcinoma, or pheochromocytoma, excess hormone secretion disrupts this balance, leading to AT dysfunction, altered adipokine secretion, and adverse metabolic profiles, including insulin resistance, visceral adiposity, and hypertension. Emerging evidence suggests that peri-adrenal AT may modulate adrenal tumor biology through endocrine and paracrine signals, and immune cell infiltration, with potential effects on disease progression and clinical presentation. Uncovering cellular and molecular mechanisms underlying the crosstalk between adrenal gland and AT may reveal new therapeutic targets for the reduction of cardiometabolic complications in patients with adrenal disorders. Here, we discuss how 2 endocrine organs-adrenal gland and AT-interact with each other under physiological and pathophysiological conditions and examine whether these interactions influence the progression of adrenal tumors and how this affects systemic metabolic health.

SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

Endocrine and neuroendocrine malignancies, including epithelial neuroendocrine neoplasms (NENs), phaeochromocytoma/paraganglioma (PPGL), adrenocortical carcinoma (ACC) and thyroid cancers, represent a heterogeneous group of tumours often characterised by dysregulated receptor tyrosine kinase signalling and with limited systemic treatment options. Cabozantinib is a multikinase inhibitor implicated in tumour angiogenesis, growth, and therapeutic resistance, and its use has been reported in many of these tumours. We performed a narrative review assessing cabozantinib monotherapy or combination regimens in patients with progressive neuroendocrine neoplasms. In NENs, monotherapy achieved a disease control rate (DCR) of up to 83% and a progression-free survival (PFS) of 8.4 months in extra-pancreatic subtypes, and 13.8 months in pancreatic subtypes. Combination therapies yielded modest efficacy with a PFS up to 13.0 months. In metastatic PPGLs, monotherapy achieved an objective response rate (ORR) of 25%, a median PFS of 16.6 months and overall survival (OS) of 24.9 months; combination with atezolizumab showed an ORR of 15.4% and a PFS of 8.4 months. In adrenocortical cancer, the DCR reached 78%, PFS up to 7.2 months, and OS up to 23.9 months. In differentiated thyroid cancer, PFS 11.4 months and OS 26.3 months; in RET M918T-mutant medullary thyroid cancer, OS improved to 44.3 months. Cabozantinib represents a promising therapeutic option across endocrine and neuroendocrine malignancies, particularly in settings with limited treatment alternatives, although the reported rates of control have not been dramatic and adverse effects not insignificant. However, it offers the possibility of exploring more effective molecular approaches, especially with biomarker-based stratification and combinatorial approaches.

SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

BACKGROUND: Differential diagnosis of adrenocortical carcinoma (ACC), pheochromocytomas, and adenomas based on contrast-enhanced computed tomography (CECT) remains a challenging task due to significant overlap in their radiological characteristics. Existing classification methods based on standard morphological criteria demonstrate limited accuracy, which may lead to misdiagnoses and inappropriate treatment strategies. The implementation of radiomics and machine learning methods has the potential to improve diagnostic accuracy; however, multiclass models covering all three types of lesions remain insufficiently studied. AIM: Development and evaluation of a machine learning model for multiclass classification of adrenal lesions into three categories (adenomas, ACC, and pheochromocytomas) based on CECT data using texture features. METHODS: A retrospective study was conducted, including 196 patients with histologically verified adrenal tumors: 28 cases of ACC, 125 pheochromocytomas, and 43 adenomas. CT images were processed using PyRadiomics to extract 106 texture features for each CT phase. To reduce the impact of scanner variability, data harmonization was performed using singular value decomposition (SVD). The XGBoost model was trained using stratified k-fold cross-validation. Model performance was evaluated using macro-averaged accuracy, class-specific accuracy, F1-score, and ROC-AUC metrics. RESULTS: The model achieved an average accuracy of 0,833 ± 0,083, a macro-averaged F1-score of 0,784 ± 0,096, and a ROC-AUC of 0,899 ± 0,061. The classification accuracy for pheochromocytomas and adenomas was 0,842 ± 0,112 and 0,872 ± 0,089, respectively, while for ACC, it was 0.647 ± 0.098. Analysis of the most informative features indicated that parameters describing homogeneity and intensity across different contrast phases were significant for classification. CONCLUSION: Radiomics and machine learning methods enable high accuracy in multiclass classification of adrenal lesions based on CECT data. However, the diagnostic accuracy for ACC remains lower, which may be related to tumor heterogeneity and sample size limitations. The results highlight the need for further research, including the integration of clinical data to improve diagnostic accuracy.

Purpose of reviewOligometastatic adrenocortical carcinoma (ACC) represents a distinct clinical subset of metastatic disease characterized by a limited tumor burden and potentially indolent biology. This review summarizes current evidence on its definition and management strategies.Recent findingsAlthough mitotane and EDP-M chemotherapy remain the backbone of systemic therapy for advanced ACC, increasing evidence supports integrating local treatments – such as surgery, stereotactic body radiotherapy (SBRT), image-guided thermal ablation (IGT), and transarterial embolization (TACE/TARE) – in selected patients. Retrospective studies suggest that individuals with ≤5 metastases or lesions <3 cm, often classified as stage IVa, achieve higher disease control rates and prolonged survival when local and systemic therapies are combined. Decision-making should consider patient fitness, tumor biology (Ki-67 index, time to recurrence), and prior treatments within a multidisciplinary framework.SummaryIf a definition of oligometastatic ACC is required, a reasonable one would include stage IVa disease or up to five metastases <3 cm. Management should rely on a multidisciplinary approach in referral centers, integrating systemic and local therapies to optimize survival and quality of life.

Bilateral adrenal metastatic renal cell carcinoma revealed by CD70- and PSMA-targeted PET imaging.

Advanced adrenocortical carcinoma with severe hypercortisolemia-role of debulking surgery