Search Results (147)

Radiopharmaceutical Theranostics defines the combination of molecularly targeted imaging and therapy in two consecutive phases. Targeted theranostic approaches are most established for the management of advanced prostate, thyroid and hepatocellular cancer, as well as neuroendocrine tumors (NETs). Adrenal malignancies present a complex challenge, requiring highly specialized management. The two primary entities addressed by targeted radiotheranostics—pheochromocytoma/paraganglioma (PPGL) and adrenocortical cancer (ACC)—consist of fundamentally distinct molecular targets and, consequently, different radiopharmaceutical agents. While most existing literature focuses on nuclear medicine–driven perspectives, the implications of theranostic advances for surgical decision-making remain underexplored. This narrative review aims to integrate available clinical evidence with multidisciplinary practice considerations, in reshaping the role of surgery in adrenal malignancies. Full article

Ectopic ACTH-secreting pheochromocytomas are rare and life-threatening endocrine tumors responsible for hypertension, paroxysmal symptoms, and Cushing’s syndrome. The cellular origin of ACTH and the tumor’s molecular characteristics remain poorly understood. Single-cell RNA sequencing was performed on tumor specimens and adjacent adrenal tissues from three patients with ectopic ACTH-secreting pheochromocytomas. Integrated bioinformatic analyses, including differential expression, functional enrichment, cell–cell communication, and pseudotemporal trajectory inference, were conducted. Key findings were supported by immunofluorescence and immunohistochemical staining. Our study integrated single-cell transcriptomic profiling with detailed clinical characterization of three cases of ectopic ACTH-secreting pheochromocytomas. All patients presented classic Cushing’s features and variable catecholamine secretory patterns. Hormone levels improved after surgical resection. Single-cell analysis revealed a complex tumor microenvironment comprising 11 distinct cell populations. Chromaffin cells expressing the ACTH precursor gene POMC were identified within the tumor cell population, suggesting that these cells may represent the source of ectopic ACTH production. This finding was further supported by immunofluorescence and immunohistochemical staining demonstrating ACTH expression in CHGA-positive chromaffin tumor cells and absence of staining for the adrenocortical marker α-inhibin. These tumor cells exhibited metabolic reprogramming characterized by upregulation of oxidative phosphorylation pathways and downregulation of adaptive immune responses. Cell–cell communication analysis suggested interactions between POMC-expressing chromaffin cells and cytotoxic immune cells. Pseudotemporal trajectory analysis further suggested that these chromaffin cells did not transition toward a steroidogenic fate. This study provided a single-cell atlas of ectopic ACTH-secreting pheochromocytomas. Our integrated analysis suggested POMC-expressing chromaffin cells may represent the cellular source of ectopic ACTH production and revealed a transcriptional signature involving metabolic activation and immune modulation that might contribute to tumor progression. These findings offered new insights into the pathophysiology of this rare disease and provided a framework for future investigations into the molecular mechanisms underlying ectopic ACTH production. Full article

This case highlights a novel genotype–phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal < 1.8 µg/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G>A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C>G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C>T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype–phenotype association, which, to our best knowledge, has not been previously reported. Full article

Adrenocortical carcinomas (ACCs) are rare, aggressive tumors often discovered incidentally. These malignancies may present with abnormal hormone secretion or, as in some cases, as non-functioning masses causing discomfort. We present a case of brain metastasis in a patient with a giant ACC. A 50-year-old man presented with headache and dizziness. A computed tomography (CT) scan showed an intracranial lesion within the parenchyma measuring 73*60*46 mm with left internal temporal involvement, abundant vasogenic edema and compressing the lateral left ventricle. Further imaging investigations identified a large necrotic tissue mass measuring 15 cm, located on both sides of the right diaphragmatic dome, in the middle posterior region. Hormonal workup was conducted and excluded a functional adrenal tumor. A CT-guided biopsy was performed, confirming ACC. Despite medical management, the patient’s condition deteriorated rapidly, with the cerebral metastasis proving fatal. This case underscores the challenges posed by advanced ACC, particularly when associated with atypical metastatic sites. Giant ACC, though rare, presents significant diagnostic and therapeutic challenges. Surgical excision with appropriate oncologic management can lead to favorable outcomes. This report contributes to the limited literature on cerebral metastases in ACC, aiming to enhance awareness among clinicians managing this rare entity. Full article

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy, for which population-level evidence regarding prognostic factors and survival conditions is limited. The available data mostly represent single-institution series, limiting their applicability. This study, therefore, assesses clinicopathological features and determines independent predictive variables of overall survival (OS) in patients with ACC using a population-based cohort. Methods: This retrospective observational cohort study used data from the Surveillance, Epidemiology, and End Results (SEER) Program between 2000 and 2022, initially identifying 1176 patients with ACC. Adult patients (≥18 years) with histologically confirmed ACC were identified using ICD-O-3 histology code 8370/3 and primary site code C74.0. Cases with zero-month survival, missing survival data, or identified only through autopsy or death certificate were excluded. To ensure dataset harmonization, patients with missing or indeterminate tumor grade and unknown stage were also excluded. After applying these inclusion and exclusion criteria, the final analytic cohort consisted of 267 patients. Data on demographic factors, stage of the disease, and treatment (surgery, chemotherapy, radiotherapy) were extracted. OS was evaluated using the Kaplan–Meier method, and independent prognostic factors were identified using Cox proportional hazards regression analysis. Results: The median OS was 54 months [95% confidence intervals (CI): 36–85]. The estimated 1-, 3-, and 5-year OS rates were 77%, 57%, and 48%, respectively. Survival differed significantly according to tumor grade, stage, and surgical treatment. In multivariable Cox regression analysis, increasing age [Hazard ratio (HR): 1.03, 95% CI: 1.02–1.04; p < 0.001], high tumor grade (HR: 2.21, 95% CI: 1.43–3.41; p < 0.001), and distant-stage disease (HR: 3.24, 95% CI: 1.95–5.38; p < 0.001) were independently associated with an increased risk of mortality, whereas surgical treatment was associated with improved survival (HR 0.53, 95% CI 0.30–0.93; p = 0.028). Chemotherapy and radiotherapy were not significantly associated with mortality. Conclusions: In this SEER-based cohort of patients with adrenocortical carcinoma, older age, high tumor grade, and distant-stage disease were independently associated with worse OS, whereas documented receipt of surgery was associated with longer OS. Treatment-related associations should be interpreted cautiously in view of the inherent limitations of registry-based data. Further prospective multicenter studies are needed to confirm these findings. Full article

Background: The differentiation of pheochromocytoma (PCC) from other adrenal lesions, particularly in incidentalomas with non-benign radiological characteristics (size > 4 cm or density > 10 HU), remains a clinical challenge. The study aimed to develop and validate an interpretable machine learning (ML) model for pairwise differentiation of PCC from adrenocortical carcinomas (ACCs) and non-functioning adrenal adenomas (NAAs) and to identify the most important clinical features. Methods: We analyzed a dataset of 50 clinical, laboratory, and radiological parameters from 123 patients with histologically verified adrenal tumors (63 PCC, 30 ACC, 30 NAA). Four classifiers—Logistic Regression (LR), Random Forest (RF), Linear Discriminant Analysis (LDA), and Extreme Gradient Boosting (XGBoost)—were trained for binary classification tasks (PCC vs. ACC, PCC vs. NAA, ACC vs. NAA) using a robust nested stratified cross-validation pipeline to ensure generalizability and avoid overfitting. Results: All four models showed strong predictive performance, with discrimination (AUC) more than 0.8. Our analysis, based on the interpretable LR model, identified the key discriminators differentiated PCC from both ACC and NAA: maximum systolic blood pressure, grade 3 hypertension, headache, palpitation, tachycardia, male sex, and concomitant gastric and duodenal ulcers. In contrast, lower back pain and general weakness were strong signs of lower probability of PCC. The tumor density specifically differentiated PCC from NAA, whereas tumor size was an important marker for distinguishing PCC and ACC. Conclusions: We developed robust ML models capable of accurately differentiating PCC from other adrenal tumors in complex cases. The models provide a clinically actionable tool for pre-surgical decision support. Furthermore, the identification of key discriminative features enhances the clinical understanding of PCC and facilitates its differential diagnosis prior to histological verification. Full article

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment. Full article

Artificial intelligence (AI) and machine learning (ML) are reshaping cancer research and care. In pediatric oncology, early evidence—most robust in imaging—suggests value for diagnosis, risk stratification, and assessment of treatment response. Pediatric endocrine tumors are rare and heterogeneous, including intra- and extra-adrenal paraganglioma (PGL), adrenocortical tumors (ACT), differentiated and medullary thyroid carcinoma (DTC/MTC), and gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Here, we provide a pediatric-first, entity-structured synthesis of AI/ML applications in endocrine tumors, paired with a methods-for-clinicians primer and a pediatric endocrine tumor guardrails checklist mapped to contemporary reporting/evaluation standards. We also outline a realistic EU-anchored roadmap for translation that leverages existing infrastructures (EXPeRT, ERN PaedCan). We find promising—yet preliminary—signals for early non-remission/recurrence modeling in pediatric DTC and interpretable survival prediction in pediatric ACT. For PGL and GEP-NEN, evidence remains adult-led (biochemical ML screening scores; CT/PET radiomics for metastatic risk or peptide receptor radionuclide therapy response) and serves primarily as methodological scaffolding for pediatrics. Cross-cutting insights include the centrality of calibration and validation hierarchy and the current limits of explainability (radiomics texture semantics; saliency ≠ mechanism). Translation is constrained by small datasets, domain shift across age groups and sites, limited external validation, and evolving regulatory expectations. We close with pragmatic, clinically anchored steps—benchmarks, multi-site pediatric validation, genotype-aware evaluation, and equity monitoring—to accelerate safe, equitable adoption in pediatric endocrine oncology. Full article

Background and Objectives: Adrenal gland tumors are frequently discovered incidentally. They remain challenging to evaluate because of their heterogeneous nature and overlapping imaging characteristics. Surgical resection continues to represent the primary treatment option for both benign and malignant lesions. This study aimed to characterize the clinical, demographic, and pathological features of adrenal tumors and to assess surgical management patterns in a tertiary referral center. Materials and Methods: A retrospective analysis was conducted on 112 patients who underwent adrenalectomy between 2015 and 2022. Demographic, clinical, radiological, and surgical data were reviewed. Histopathological findings were classified as benign tumors, primary adrenal malignancies, or adrenal metastases. Both laparoscopic adrenalectomy and open surgery were performed. The operative approach was determined by tumor characteristics and oncologic considerations. Results: Among the 112 patients, 48% had benign adrenal tumors, 32% had adrenal metastases, and 19.6% were diagnosed with primary adrenal malignancies. Most patients with adrenocortical carcinoma were women over 55 years of age. Benign lesions were predominantly managed with simple adrenalectomy and minimally invasive techniques, while malignant tumors frequently required complex oncologic resections and open surgical approaches. Distinct metastatic patterns were observed, with renal cell carcinoma representing the most common primary source of adrenal metastasis. Conclusions: Adrenal tumors demonstrate marked demographic and pathological variability. Surgical resection remains essential for definitive diagnosis and treatment, underscoring the importance of tailoring the operative approach. Minimally invasive surgery is appropriate for benign lesions, whereas open adrenalectomy is preferred for malignant or advanced tumors, where surgical expertise is critical to achieving optimal oncologic outcomes. Full article

Two old cases of adrenocortical tumors with contradictory diagnostic findings and opposite conclusions are revisited in light of the recent WHO guidelines, as follows: a 34-year-old woman and a 15-month-old girl, both with severe virilization and adrenal mass at radiological investigation, studied in 1966 and 1977, respectively, in accordance with the diagnostic procedures available in those years. Dynamic hormonal findings seemed to exclude malignancy in the woman but were in favor of malignancy in the girl. Instead, a 305 gr mass on the right adrenal gland was removed in the woman and histopathologically verified as adrenocortical carcinoma, whereas in the girl, a 140 gr mass in the right adrenal gland was removed and histopathologically verified as adrenocortical adenoma. After a six-month span of clinical condition improvement, the woman developed recurrence with multi-organ metastases. Mitotane treatment temporarily improved her condition, but it progressively worsened until her death 11 months later. The girl instead showed progressive improvement in clinical and laboratory findings until complete normalization in 18 months. The use of dated radiological and laboratory investigations suggests caution against generalization of our assumption; however, these cases suggest that only histopathological findings from surgical specimens ensure a correct diagnosis of adrenocortical masses. Full article

Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel–Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li–Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps. Full article

The AP-2 family is a group of key regulators in cancer, yet their relationship with intratumoral microbes remains undefined. The present pan-cancer workflow leveraged TCGA transcriptomic data to correlate expression of AP-2 representatives with bacterial abundance on the genus and species level, followed by cohort-specific survival modeling, clinical profiling, differential expression, weighted co-expression analysis, and chromatin proximity tests with AP-2 enrichment. Significant correlations between microbiota and AP-2 were observed in 18 of 33 analyzed tumor types; TFAP2E-AS1 was most recurrent among AP-2 members, and Halomonas was most recurrent among genera. Further species-level verification and prognostic importance nominated three promising pairs: Paraburkholderia fungorum–TFAP2E in adrenocortical carcinoma (ACC), Actinomyces oris–TFAP2E in diffuse large B-cell lymphoma (DLBC), and Cutibacterium granulosum–TFAP2B in stomach adenocarcinoma (STAD). An attempt to define a consensus expression signature driven by microbiota and AP-2, yet independent of the specific species or family member, revealed genes regulating various biological processes and pathways. ACC and DLBC shared a consensus expression program, whereas STAD diverged; chromatin analysis showed AP-2 motifs near microbe-responsive genes in ACC and DLBC but not STAD, supporting cohort-specific regulation. Collectively, AP-2 family members emerge as plausible mediators of tumor microbiota–host interplay, warranting further mechanistic and translational research. Full article

Background: Feminizing adrenocortical tumors (FATs) are an exceedingly rare subset of adrenal neoplasms, typically affecting adult men and characterized by an excess of estrogen, suppressed gonadotropins, and gynecomastia. Most FATs are malignant, with a poor prognosis and a high risk of recurrence. Case Presentation: We report the case of a 24-year-old male with bilateral gynecomastia, abdominal mass symptoms, and one year of unexplained infertility. A hormonal evaluation revealed elevated estradiol (90.1 pg/mL) and suppressed ACTH (2.6 pg/mL), with inappropriately normal cortisol levels (12.1 µg/dL). Imaging identified a right adrenal mass. The patient underwent open adrenalectomy, and histopathology confirmed stage II adrenocortical carcinoma (T2NxM0) with autonomous estradiol secretion, negative margins, and a Ki-67 index of 10%. Postoperatively, gonadal function normalized, and infertility resolved at two months. The multidisciplinary tumor board considered but did not initiate adjuvant mitotane, given the completely resected low-stage disease. Conclusions: This case illustrates the rare presentation of feminizing adrenocortical carcinoma with reversible infertility and highlights the importance of early recognition and close surveillance. In addition, our literature review of 12 male cases reported between 2015 and 2025 emphasizes gynecomastia as the hallmark presentation and discusses emerging evidence supporting active surveillance as a potential alternative to adjuvant mitotane in selected low-risk patients. Full article

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Complete tumor resection (R0) is critical for prognosis and may require multivisceral resection in locally advanced cases. However, data on outcomes after multivisceral resection for ACC remain limited. This study evaluates the perioperative and oncologic outcomes of patients undergoing multivisceral resection for suspected ACC. Methods: We retrospectively analyzed 21 patients who underwent multivisceral resection with curative intent for suspected ACC. Three were later diagnosed with other tumor entities (sarcoma, non-small cell lung carcinoma metastasis and ganglioneuroma). The remaining 18 patients with histologically confirmed ACC were compared with 19 patients who underwent isolated adrenalectomy during the same study period. Results: Patients undergoing multivisceral resection were significantly younger (p = 0.003), had larger (p < 0.001) and more advanced tumors according to ENSAT classification (p < 0.001). All but one had open surgery; laparoscopic or hybrid approaches were more common in the isolated adrenalectomy group. Multivisceral resections were associated with longer operative times (p = 0.002), all required an ICU admission (p < 0.001), and had longer hospital stays (p = 0.001). Lymphnode metastases were observed only in the multivisceral group (p = 0.002). No significant differences were found in complication rates (p = 0.081), resection status (p = 0.091), progression-free survival (p = 0.095), or overall survival (p = 0.71). Conclusions: Multivisceral resection is a safe and feasible approach in specialized centers and may achieve comparable oncologic outcomes to isolated adrenalectomy, even in patients with more advanced disease. It should be considered when R0 resection is required and technically achievable. Full article

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with poor prognosis, particularly in metastatic cases. The Ki-67 proliferation index is a recognized marker of tumor aggressiveness, yet its role in guiding diagnostic imaging and surgical decision-making remains underexplored. This study evaluates Ki-67’s predictive value for metastasis at diagnosis, leveraging artificial intelligence (AI) to inform personalized, minimally invasive strategies for ACC management. Methods: We retrospectively analyzed 53 patients with histologically confirmed ACC from the Adrenal-ACC-Ki67-Seg dataset in The Cancer Imaging Archive. All patients had Ki-67 indices from surgical specimens and preoperative contrast-enhanced CT scans. Descriptive statistics, t-tests, ANOVA, and multivariable logistic regression evaluated associations between Ki-67, tumor size, age, and metastasis. Random Forest classifiers—with and without the Synthetic Minority Oversampling Technique (SMOTE)—were developed to predict metastasis. A Ki-67-only model served as a baseline comparator. Model performance was assessed using the area under the curve (AUC) and DeLong’s test. Results: Patients with metastatic disease had significantly higher Ki-67 indices (mean 39.4% vs. 21.6%, p < 0.05). Logistic regression identified Ki-67 as the sole significant predictor (OR = 1.06, 95% CI: 1.01–1.12). The Ki-67-only model achieved an AUC of 0.637, while the SMOTE-enhanced Random Forest achieved an AUC of 0.994, significantly outperforming all others (p < 0.001). Conclusions: Ki-67 is significantly associated with metastasis at ACC diagnosis and demonstrates independent predictive value in regression analysis. However, integration with machine learning models incorporating tumor size and age significantly improves overall predictive accuracy, supporting AI-assisted risk stratification and precision imaging strategies in adrenal cancer care. Full article