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BACKGROUND: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. METHODS: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n = 429) and ACC (n = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. RESULTS: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p = 0.002, p = 0.007, and p = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n = 10) and inactive-ACA (n = 215) (p = 0.040 and p = 0.031, respectively). CONCLUSION: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

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INTRODUCTION: Adrenocortical tumors (ACTs) are rare endocrine neoplasms in children, with functional ACTs being more prevalent than non-functional types. Clinical manifestations typically include virilization, Cushing's syndrome, and hyperaldosteronism. Surgical intervention is the primary treatment for ACTs, with a significant risk of recurrence in adrenocortical carcinoma even after complete resection. PRESENTATION OF CASE: This case presentation describes a 3.5-year-old female with generalized hirsutism and clitoral hypertrophy, leading to the discovery of a left adrenal tumor. The child underwent adrenalectomy, revealing a benign adrenal cortical adenoma. Unfortunately, due to loss of follow-up, the child later presented with pulmonary metastases and passed away, preventing further investigation into the source of metastases. DISCUSSION: Adrenocortical tumors are uncommon in children, with the classification of ACTs into adenomas and carcinomas. To our knowledge, this is the third case of an adrenocortical tumor in a child in Syria. We highlight the challenges in managing pediatric ACTs and emphasize the importance of timely intervention and close monitoring to improve outcomes. Regular follow-up is crucial to detect complications early and optimize treatment strategies, especially considering the unpredictable behavior of these tumors. CONCLUSION: This case confirms that distinguishing between adrenocortical adenoma and carcinoma can be challenging even histologically. Therefore, it is necessary to follow up after treating each case of adenoma in a child to prevent major complications.

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Introduction: Patients are qualified for an adrenalectomy due to endocrine or oncologic reasons. Final histopathological diagnoses include a wide spectrum of more than a dozen entities. The aim of this study was to compare preoperative and postoperative diagnoses of patients undergoing adrenalectomy to determine the level of diagnostic accuracy, as well as sex and age of patients. Material and methods: A group of 214 patients (230 specimens in total) operated on in a single center was studied and their demographic and pathological data were investigated. Results: The majority of diagnoses were characterized by both high positive predictive value and sensitivity, excluding pheochromocytoma (60.0% and 67.7%, respectively) and adrenal cyst (100% and 37.5%, respectively). Patients operated on due to Cushing's syndrome were statistically significantly more often females (p = 0.009), while those with metastases (diagnosed both pre- and postoperatively) were more often males (both p = 0.001). Patients qualified due to non-functioning tumors were older than those with Cushing's or Conn's syndrome (p = 0.044 and p = 0.002, respectively). Conclusions: The lowest diagnostic accuracy is observed in cases of pheochromocytoma and adrenal cyst. Meticulous preparation of the patient for hormonal tests, including discontinuation of certain medications, is essential for obtaining accurate results. The diagnosis of Cushing's syndrome is more prevalent in females, while metastasis syndrome is more prevalent in males. Adrenocortical carcinoma may initially be diagnosed as a non-functioning tumor (1.6% of such cases) or a recurrence of a previously resected tumor, which should always raise a suspicion of a malignant neoplasm.

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Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple organs. Although being a dominantly inherited monogenic disease, disease phenotypes are unpredictable and differ even among members of the same family. There is growing evidence for the role of modifier genes in the alteration of the course of this disease. However, genome-wide screening data are still lacking. In our study, we addressed the different outcomes of the disease, focusing on pituitary and adrenocortical tumors. By means of exome sequencing we identified the affected signaling pathways that segregated with those symptoms. Most significantly, we identified damaging alterations in numerous structural genes responsible for cell adhesion and migration. Additionally, in the case of pituitary tumors, genes related to neuronal function, survival, and morphogenesis were repeatedly identified, while in patients with adrenocortical tumors, TLR10, which is involved in the regulation of the innate immunity, was commonly modified. Our data show that using exome screening, it is possible to find signatures which correlate with the given clinical MEN1 outcomes, providing evidence that studies addressing modifier effects in MEN1 are reasonable.

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Background and Aims: Superior imaging techniques have increased the recognition of adrenal pathology. Distinguishing benign from malignant adrenocortical tumors is not always easy. Several criteria and immunohistochemical markers have been discovered which help to differentiate between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). Our aim here was to evaluate the diagnostic and prognostic role of steroidogenic factor-1 (SF-1) in adult adrenocortical tumors (ACT) diagnosed using the Weiss criteria. In this cohort, we have also analyzed Ki67 and p53 expression and the extent of agreement between SF-1 and Ki-67. Methodology: This was a retrospective, observational study comprising 24 cases of adult ACT over 10 years. Immunohistochemical staining for SF-1, Ki67, and p53 was done in all the cases, and the results correlated with the morphological diagnosis made using Weiss criteria. Results: SF-1 was 100% sensitive and 80% specific as a marker of malignancy. Increased SF-1 expression correlated with worse survival. There was a moderate degree of agreement between Ki-67 labeling-index and SF-1 as a marker of malignancy with the kappa coefficient being 0.75. The sensitivity of p53 was lower than Ki67 in diagnosing ACC. Conclusion: In adult ACTs, SF-1 has diagnostic significance and prognostic implication. SF-1 is a crucial, dosage-dependent survival factor in ACC. There is a moderate extent of agreement between Ki-67 and SF-1 as a marker of malignancy.

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Pediatric adrenocortical tumor (ACT) is a rare and aggressive neoplasm, with incidence in southern and southeastern Brazil 10-15 times higher than worldwide. Although microRNAs (miRNAs) have been reported to act as tumor suppressors or oncogenes in several cancers, the role of miR-149-3p in ACT remains unknown. In this study, we evaluated the expression of miR-149-3p in 67 pediatric ACT samples and 19 non-neoplastic adrenal tissues. The overexpression of miR-149-3p was induced in H295A cell line, and cell viability, proliferation, colony formation, and cell cycle were assessed by in miR-149-3p mimic or mimic control. In silico analysis were used to predict miR-149-3p putative target genes. CDKN1A expression at the mRNA and protein levels was evaluated by qRT-PCR and western blot, respectively. Higher miR-149-3p expression was associated with unfavorable ACT outcomes. Compared to the mimic control, miR-149-3p overexpression increased cell viability and colony formation, and affected cell cycle progression. Also, we identified CDKN1A as a potential miR-149-3p target gene, with decreased expression at both the gene and protein levels in miR-149-3p mimic cells. Collectively, these findings suggest that miR-149-3p promotes H295A cell viability by downregulating CDKN1A and provide evidence that miR-149-3p may be useful as a novel therapeutic target for pediatric ACT.

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ARMC5: is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing's syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.

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Adrenocortical cancer is a rare malignancy of the endocrine system. Therefore, when this malignancy presents with metastatic disease, this leads to further difficulties in management. Due to the rare and ambiguous nature of this malignancy, diagnosis is generally made at later stages, with limited options for patients. Symptoms may include weight gain/loss, muscle weakness, abdominal discomfort/bloating, hyperglycemia, hypertension, electrolyte imbalance, hirsutism and virilization in females, gynecomastia and hypogonadism in males. Due to the variety of conditions presenting with one or more of these symptoms, diagnosis can be difficult. Many adrenocortical tumors, malignant and benign, are usually detected incidentally on imaging performed for evaluation of another condition, also known as "incidentalomas." Here, we present a rare case of metastatic adrenocortical malignancy in a 56-year-old female patient who presented with isolated recurrent episodes of hypokalemia.

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Pure androgen-secreting adrenocortical tumors (PASATs) are rare entities. Their clinical presentations include virilizing features that vary based on age and gender. The pathogenesis of this tumor is still unclear, with around 50% of such tumors being malignant. Imaging characteristics of the tumor on CT/MRI including size, heterogenicity, and contrast wash-out time are used to predict malignancy. Surgical excision is recommended for all functional adrenal tumors. In this report, we discuss a case of a 68-year-old postmenopausal female presenting with hyperandrogenism and was found to have a 7-cm, PASAT that raised suspicion for malignancy on CT scan, but was determined to be benign on surgical pathology.

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Objective: Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation. Design and methods: A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method. Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT. Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass. Significance statement: Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.

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FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.

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The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang-Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang-Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang-Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis.

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Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2, TOP2A, and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2, VSNL1, and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors.

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Objective: Estrogen-secreting adrenocortical tumors (ACTs) are quite rare with feminizing adrenocortical tumors (FATs) accounting for 0.37-2% of all ACTs. The aim was to evaluate clinical and hormonal characteristics of FATS as well as treatment options and follow-up in the pediatric age group. Methods: Medical records of children with ACTs presenting to a single center in the last two decades were reviewed. Literature review within Pubmed revealed 34 pediatric patients (22 boys) with FAT among 192 articles. Results: Among the 25 children presenting with ACTs in the last two decades, two new pediatric cases of FAT were identified, one benign and the other malignant, in two genders with different clinical presentations. Literature review showed that FATs are extremely rare tumors that are most commonly seen in men and boys presenting with gynecomastia. FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. While boys present with contrasexual pseudopuberty signs, girls present with isosexual pseudopuberty. A high estrogen level strongly supports diagnosis, while elevations in other adrenal hormones may be seen. FATs are usually malignant in adults and prognosis is generally very poor. However, in children approximately half are benign although assessment of malignant potential depends on clinical behavior of the tumor. FATs are very unpredictable so even after surgery long-term follow-up is required. FATs presenting in childhood may have a better prognosis than adult presentation tumors as most FATs in children are followed without recurrence of tumor. Conclusion: FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. FATs in childhood may have a better prognosis than in adult males.

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Pediatric adrenocortical tumors (ACTs) are rare entities with an incidence of 0.2% of all pediatric tumors. Only two cases of antenatally detected ACT have been reported in the literature. Our case is the first report of an antenatally detected suprarenal mass which manifested with postnatal virilizing features and was proven to be adrenocortical adenoma on histology.

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PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 - 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 - 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

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BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome characterized by congenital malformations and predisposition to embryonic tumors. Loss of methylation of imprinting center 2 (IC2) is the most frequent alteration and rarely associated with tumors compared to paternal uniparental disomy of chromosome 11 (UPD(11)pat) and gain of methylation of imprinting center 1. METHODS: Our study aimed to describe the clinical, histopathological and genetic characteristics of two patients and establish genotype-phenotype correlations. The clinical diagnosis was based on the criteria defined by the international expert consensus of BWS. Molecular study of 11p15.5 methylation status was assessed using methylation-specific-multiplex ligation probe amplification (MS-MLPA). RESULTS: Patients were aged 12 months and 3 months and fulfilled the clinical score of BWS. MS-MLPA showed molecular alterations consisting of loss of methylation in IC2 (IC2-LOM) at the maternal allele for one patient and a mosaic UPD(11)pat for the second patient in whom follow-up at 6months revealed adrenocortical carcinoma (ACC) with low grade of malignancy. Molecular subtypes guide the follow-up and tumor surveillance, our major concern. CONCLUSION: We have to take into account the psychological impact of a possible tumor whatever the underlying mechanism is. Nevertheless, the tumor risk remains high for UPD(11)pat. Our study extended the phenotype of BWS with absence of macrosomia in Tunisian patients, contrasting with literature, and added a supplementary case of ACC in the tumor spectrum of BWS patients with UPD(11)pat.

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INTRODUCTION: Pediatric adrenocortical carcinoma (ACC) is a rare malignancy, encompassing less than 0.2% of all childhood malignancies. Due to the scarcity of this diagnosis, it is often managed according to guidelines established for adults, as there is a lack of reliable evidence regarding optimal adjuvant treatment options for pediatric patients. It is our aim to identify recent treatment trends as well as clinical and tumor characteristics and their impact on overall survival. METHODS: Using the National Cancer Data Base (NCDB), this study identified 49 patients under 18 years old with localized ACC (M0) undergoing adrenalectomy from 2004 to 2017. Kaplan-Meier analysis was performed to determine overall survival (OS) from patient characteristics and treatments received. Comparison of survival was performed using the log rank test. RESULTS: The median age of our cohort was 3 years old with a slight female predominance of 61%. The median tumor size was 9.4 cm, and patients older than 4 years were significantly (p = 0.03) more likely to present with larger tumors (11.33 cm vs 8.76 cm). Adjuvant treatment in the form of systemic therapy was administered in 20 of 49 (41%) patients and radiation therapy in 2 of 49 (4%) patients. Three-year OS for patients 4 years old and younger was 92.6% vs 61.8% for those older than 4 years (p = 0.002). Patients presenting with tumor size ≥9 cm had worse three-year OS compared to those with tumors <9 cm (95.24% vs 67.1% respectively, p = 0.02, Fig. 1). In patients with tumors ≥ 9 cm, younger children age 0-4 years had significantly (p = 0.04) higher OS rates than older children age 5-17 years. CONCLUSIONS: ACC is a rare pediatric malignancy with a female predominance. Those older than 4 years and those with presenting tumor size ≥9 cm have decreased overall survival rates after adrenalectomy for localized disease. Additionally, children older than 4 have poorer prognosis, even after controlling for larger tumor size. This is the largest contemporary series of localized pediatric ACC to date. However, multi-institutional prospective cohort or randomized-controlled trials are necessary to better evaluate relevant prognostic factors and the role of adjuvant therapies following adrenalectomy.

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Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed.