Case Of Adrenocortical Carcinoma Research Articles

Adrenal cortical carcinoma: Paediatric aspects - literature review.

Adrenocortical carcinoma (ACC) is arare malignancy in children. Because of this, each patient with suspected ACC requires individualised management, which should be determined at ameeting of ateam of multidisciplinary experts in the field. To summarise data on symptoms, genetic predisposition, and diagnostic procedures for ACC in children. Papers were searched in the PubMed database to identify published randomised clinical trials, reviews, systematic reviews, meta-analyses, and case reports. Most cases of ACC in children occur under the age of 5 years. The most common presenting symptom in 60-80% of paediatric patients is rapidly progressive virilisation. Diagnostics are based on laboratory and imaging evaluation. The mainstay of treatment is surgery, with laparotomy being the preferred method of surgery. Diagnosis is based on histological examination of surgically removed tissue. The Wieneke index is most commonly used in paediatric practice. However, some cases are still classified as "indeterminate histology". Predisposing genetic factors are found in most children with ACC, most commonly amutation of the TP53 gene. Patients should be diagnosed in large clinical centres with experience in this field. The treatment strategy should be individualised. Genetic testing for TP53 gene mutations is indicated in patients with ACC.

Laparoscopic surgery for adrenocortical carcinoma: Estimating the risk of margin-positive resection.

Over recent years, there has been increasing adoption of minimally invasive surgery (MIS) in the treatment of adrenocortical carcinoma (ACC). However, MIS has been associated with noncurative resection and locoregional recurrence. We aimed to identify risk factors for margin-positivity among patients who undergo MIS resection for ACC. We hypothesized that a simple nomogram can accurately identify patients most suitable for curative MIS resection. Curative-intent resections for ACC were identified through the National Cancer Database spanning 2010-2018. Trends in MIS utilization were reported using Pearson correlation coefficients. Factors associated with margin-positive resection were identified among preoperatively available variables using multivariable logistic regression, then incorporated into a predictive model. Model quality was cross validated using an 80% training data set and 20% test data set. Among 1260 ACC cases, 38.6% (486) underwent MIS resection. MIS utilization increased over time at nonacademic centers (R = 0.818, p = 0.007), but not at academic centers (R = 0.009, p = 0.982). Factors associated with margin-positive MIS resection were increasing age, nonacademic center (odds ratio [OR]: 1.8, p = 0.006), cT3 (OR: 4.7, p < 0.001) or cT4 tumors (OR: 14.6, p < 0.001), and right-sided tumors (OR: 2.0, p = 0.006). A predictive model incorporating these four factors produced favorable c-statistics of 0.75 in the training data set and 0.72 in the test data set. A pragmatic nomogram was created to enable bedside risk stratification. An increasing proportion of ACC are resected via minimally invasive operations, particularly at nonacademic centers. Patient selection based on a few key factors can minimize the risk of noncurative surgery.

FRI191 Changes In The Incidence And Geographical Distribution Of Adrenocortical Carcinoma: A Retrospective Analysis Of A State Cancer Registry

Abstract Disclosure: V.B. Brondani: None. A.M. Griffin: None. T.J. Owen: None. K.W. Merriman: None. J.M. Varghese: None. C. Jimenez: None. S.G. Waguespack: None. P.H. Graham: None. M.T. Campbell: None. M.M. Hassan: None. M.A. Habra: None. Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of 0.102 cases per 100,000 persons per year in the United States. At our tertiary cancer center, we have observed increasing numbers of cases, but to date there has been no study exploring ACC incidence at a populational level to validate our observations. Furthermore, the possibility of geographic ACC clusters has not been studied. Our objectives were to evaluate the incidence and geographical distribution of ACC cases in Texas. Methods: Cases of ACC between 2000 and 2018 were retrospectively identified from the Texas Cancer Registry (TCR). Cases were registered in 110 of Texas' 254 counties (43.3%), representing 92.74% of the total population of Texas. SEER Stat software was used to pool demographic and clinical characteristics and calculate incidence rates. Kaplan-Meier overall survival curve and Pearson's correlations were calculated using SPSS. P values &amp;lt; .05 were considered significant. ACC county-level heatmaps were created with Tableau software to identify clusters. Breast, prostate, lung cancer incidences and their geographic distribution were compared to ACC data. Results: TCR registered 448 cases of ACC in the study period, with a median of 23 new cases/year (range 14-33). Thirty-three (7.4%) patients were aged 19 years or younger (15 were under 5 years), 293 (65.4%) patients were between 20 and 64 years, and 122 (27.23%) were 65 years or older. The majority were female (270 cases [60.3%]), and White (393 [87.7%]). One hundred (22.3%) patients were Hispanic. In 155 evaluable cases, the proportions of patients with stage I, II, III, and IV disease at diagnosis were 7.7%, 27.7%, 16.1%, and 48.4%, respectively. The median overall survival was two years (range, 0-19 years). The mean adjusted population ACC incidence rate was 0.104 per 100,000 per year (std = 0.005; 95% CI, 0.092-0.116). Seven counties (6.3%) accounted for 215 (48.0%) cases, with more than 10 cases each (median, 34 cases per county; range, 11-66) and a median standardized incidence ratio (SIR) of 0.1 (range, 0.0-0.9). One hundred three counties (93.7%) accounted for the remaining 233 cases (52%), with fewer than 10 cases per county (median, 1 case; range, 1-9 cases). The highest SIRs (corresponding to &amp;gt;10, range, 11.2-30.8) were found in counties with a median population of fewer than 14,000 and with only one reported case. We could not detect any geographic clustering of ACC. Counties with a high frequency of breast, prostate, lung cancer cases also had more cases of ACC (Pearson correlation .982, .981, and .982, respectively; P &amp;lt; .01 for all tests). Conclusion: The incidence of ACC in Texas remained relatively stable through the years and consistent with the US annual incidence. We did not observe any obvious ACC cluster, and SIRs may not be useful for analyzing this rare disease. Presentation: Friday, June 16, 2023

FRI222 Large Non-functional Adrenocortical Carcinoma In A Patient With History Of Occupational Radiation Exposure

Abstract Disclosure: A. Makawi: None. G. Elshimy: None. N. Martinez de Andino: None. A. Bolduc: None. Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.1-2.0 cases/per million per year. Up to 70% of tumors present with biochemically apparent adrenocortical hormone production. Diagnosis requires investigation of clinical, biological, and imaging features with measurement of steroid hormones key for evaluation. Anderson’s syndrome is commonly seen. Research has shown ACC is driven by several molecular changes that include the inactivation of tumor suppressor genes and activation of different oncogenes, DNA mutations, and epigenetic changes. The widely used staging of ACC is by the European Network of Study of Adrenal Tumors (ENSAT) as it is correlated with clinical outcomes. Here we present a case of a non-secretory ACC noted for 10 years with growth up to 7.5 cm in a patient with history of occupational radiation exposure. Case Presentation: Patient is a 57-year-old white male with history of colon polyps, basal and squamous cell carcinoma, and hypertension diagnosed 10 years prior, on amlodipine 5 mg and lisinopril 20 mg daily who presented to adrenal clinic for evaluation of a 7cm left adrenal mass that had grown from 1.8cm 10 years prior, to 5.7cm 7 years later to 7.5cm at time of surgery. He had symptoms of fatigue and occasional lightheadedness with no other signs or symptoms of Cushing's or pheochromocytoma. Family history noncontributory. He has a history of occupational exposure to radiation working at a nuclear reactor. Workup for adrenal incidentaloma included assays of serum normetanephrine which was increased at 1.2 nmol/L (reference &amp;lt;0.9 nmol/L) with normal metanephrine less than 0.20 nmol/L, normal DHEA-S of 52 mcg/dL, normal ACTH of 16 pg/mL and negative 1mg dexamethasone suppression test with serum cortisol suppressed to 0.78 mcg/dL. CT scan adrenal protocol showed a heterogeneous 7.7x6.6 cm left adrenal mass with 30 HU, with an absolute adrenal washout of 39% and relative washout of 31.4%. He then underwent left adrenalectomy on 12/16/2022. The tumor measured 7.5cm with pathology of low-grade ACC with staging of pT3. Margins were negative for carcinoma but microscopic angioinvasion and capsular invasion were noted. Postoperatively, the patient had resolution of his symptoms with marked improvement in BP. We continue to follow him in clinic for postoperative management. He has been referred for genetic testing with results pending. Discussion: The prognosis of ACC has been believed to be poor due to the low prevalence and sample size of ACC patients, but recent studies have shown that ACC presentation, survival, and prognosis are heterogeneous. Only 20-30% of ACC are nonfunctional. It is important to note that only 30% of ACC cases are curable at early stages, further impacting the poor prognosis. The goal of this report is to bring further attention to the timely assessment and personalized management of ACC given the evolving knowledge base. Presentation: Friday, June 16, 2023

Angiotensin II-activated mTOR pathway passes through mitochondrion in adrenocortical cells: A role of acyl CoA synthetase.

For many decades, mitochondrion has been traditionally considered as the powerhouse of the cell. In addition to energy production, this intracellular organelle plays an important role in regulating programmed cell death (apoptosis), calcium homeostasis, thermogenesis, and stress response. All of these pleiotropic functions are mostly mediated by signaling pathways that pass through the mitochondrial membranes and matrix. Not surprisingly, members of the nuclear receptor family of transcription factors have been detected in mitochondrion following hormone-induced activation (1). A similar phenomenon seems to occur with members of the mammalian/mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), indicating that subcellular compartmentalization of signaling proteins matters a lot (2). mTORC1 and mTORC2 are 2 distinct protein complexes that both consist of an intracellular serine-threonine kinase, named mTOR, which is activated by the PI3K-Akt pathway. mTORC1 is activated by several growth factors, including the epidermal growth factor (EGF) and the insulin-like growth factor 1/2, and plays a fundamental role in protein and lipid biosynthesis, ribosome biogenesis, as well as in the aging of organisms (2). On the other hand, mTORC2 is also activated by growth factors and participates in cell survival, cytoskeletal organization, metabolism, and cell migration (2). The protein members of both mTORC complexes have been detected in many subcellular compartments, including cytoplasm and nucleus, as well as in lysosomes, peroxisomes, and the Golgi apparatus. However, the mitochondrial localization of these proteins had not been clearly documented until recently (2). Independently of subcellular compartmentalization, Su et al demonstrated that the mTOR signaling cascade was overexpressed in the zona glomerulosa of patients with aldosterone-producing adenomas, indicating that mTOR inhibitors might be used to treat hyperaldosteronism (3). Soon after, De Martino and collaborators investigated the expression of the mTOR pathway in normal adrenal tissues, adrenal hyperplasia, adrenocortical adenomas, and adrenocortical carcinomas (4). They also studied the effects of sirolimus, a well-known mTOR inhibitor, on survival and cortisol secretion in a number of primary cultures of human adrenocortical tumors. Interestingly, the authors found that the mTOR pathway was activated in a subset of adrenocortical tumors and that certain cases of adrenocortical carcinomas were sirolimus-responsive (4), indicating that mTOR inhibitors might be further used to suppress adrenal steroid production. Furthermore, although angiotensin II (Ang II) had been shown to activate the mTOR pathway in esophageal carcinoma (2), a similar Ang II-induced activation of the mTOR signaling cascade had not been reported in adrenal cortex.

Positive Correlation Between 18 F-FDG Uptake and Tumor-Proliferating Antigen Ki-67 Expression in Adrenocortical Carcinomas.

Adrenocortical carcinoma (ACC) is an extremely rare endocrine malignancy, which cannot always be diagnosed during conventional radiology and hormonal investigations. 18 F-FDG PET could help predict malignancy, but more data are necessary to support future guidelines. A cohort of 63 patients with histologically proven ACC (n = 55) or metastatic ACC with steroid oversecretion (n = 8) was assembled. All patients underwent an 18 F-FDG PET, and the SUV max and the adrenal-to-liver SUV max ratio were calculated. The 18 F-FDG PET parameters were compared with clinical, pathological, and outcome data. Fifty-six of 63 patients (89%) had an ACC with an adrenal-to-liver SUV max ratio >1.45, which was a previously defined cutoff value to predict malignancy with 100% sensitivity. Seven ACCs (11%) had a lower uptake (adrenal-to-liver SUV max <1.45), most of them with a proliferation marker Ki-67 expression level <10%. A positive correlation between 18 F-FDG PET parameters (SUV max and adrenal-to-liver SUV max ratio) and tumor size, ENSAT (European Network for the Study of Adrenal Tumors) staging, total Weiss score, and the Ki-67 was found. The strong correlation between SUV max and Ki-67 ( r = 0.47, P = 0.0009) suggests a relationship between 18 F-FDG uptake levels and tumor proliferation. No statistically significant associations between outcome parameters (progression-free or overall survival) and 18 F-FDG PET parameters were found. This large cohort study shows that most cases of ACC demonstrate high 18 F-FDG uptake. However, the positive correlation observed between SUV max and Ki-67 expression levels seems to explain the possibility of identifying some ACC with a low or inexistent 18 F-FDG uptake. These findings have practical implications for the management of patients with an adrenal mass.

Angiogenesis Imaging of Adrenocortical Carcinoma with Ga-68-NODAGA-RGD Positron Emission Tomography: Opening New Horizons in Multimodality Imaging from Theranostic Perspective.

A 53-year-old female, with a known case of adrenocortical carcinoma (ACC), underwent F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for initial staging, which revealed FDG avid large left suprarenal mass contiguous with hypermetabolic tumor thrombus in the inferior vena cava (IVC) through the left renal vein. Thereafter, she underwent angiogenesis imaging using Ga-68-NODAGA-RGD PET/CT, which showed similar avid tracer uptake in both primary and IVC thrombus. Demonstration of RGD avidity in ACC in this case opens a new horizon for targeted radionuclide therapy (e.g., Lu-177 RGD) in selected patients, who may have limited therapeutic options.

Ferroptosis Biomarkers for Predicting Prognosis and Immunotherapy Efficacy in Adrenocortical Carcinoma

Numerous studies have suggested that ferroptosis plays an important regulatory role in cancer cell death. Nonetheless, the potential effects of ferroptosis regulators on the prognosis, the expression of immunomodulatory factors in the tumor microenvironment and on the efficacy of immunotherapy in adrenocortical carcinoma (ACC) remain largely unknown. Public ACC datasets were used to investigate the relationship between ferroptosis regulators and prognosis and clinical features. A ferroptosis scoring system was established for individual cases of ACC using principal component analysis algorithms. Hub ferroptosis-related genes involved in immunoregulation and immunotherapy efficacy in ACC were further identified. Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to prognosis in ACC. A ferroptosis scoring system was developed based on ACSL4, FANCD2, and SLC7A1 expression, and the ferroptosis regulators could serve as an independent prognostic factor for ACC. Further analyses indicated that the ferroptosis score integrated with the tumor mutation burden (TMB), and immune-checkpoint gene expression could predict prognosis in ACC. RNA isolation and reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2, and SLC7A1 between ACC and normal tissues. Furthermore, FANCD2 was significantly related to immunotherapy efficacy and prognosis in ACC. Our study demonstrated that ferroptosis was significantly associated with prognosis, clinical characteristics, immune-checkpoint gene expression, and tumor microenvironment immune cell infiltration in ACC. The current study provides comprehensive evidence for further research on ferroptosis regulators in ACC and provides new insight into the epigenetic regulation of the antitumor immune response.

Expression of glucocorticoid receptor (GR) and clinical significance in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine tumor, and most cases present with hormone excess with poor prognosis. Our research aims to determine the clinical and biological significance of glucocorticoid receptor (GR) expression using large cohorts of ACC patients. Immunohistochemistry was used to assess the expression of GR in 78 ACC cases from the West China Hospital (WCH) cohort. RNA-seq data were retrieved from The Cancer Genome Atlas database (TCGA, n=79). Clinicopathological and follow-up data were obtained from two cohorts. The correlation between the GR gene and tumor immune status was estimated using TIMER and GEPIA2. Kaplan–Meier analysis was performed to identify the prognostic value of GR in ACC. In the WCH cohort, positive nuclear GR staining was identified in 90% of the primary ACC cases. Cortisol-secreting ACCs demonstrated significantly lower GR protein expression than did nonfunctioning tumors (P<0.001). This finding was validated by the mRNA data analysis of the TCGA cohort (P = 0.030). GR expression was found to be positively correlated with the immune cell infiltration level and immune-checkpoint-related gene expression in ACC. Survival comparison and multivariate analysis showed that GR expression is an independent prognostic predictor of disease-free survival and overall survival in ACC patients in both cohorts. Our findings suggest that low GR expression is significantly correlated with excess cortisol, immune signatures and poor survival in ACC patients. We propose that GR signaling may play an important role in ACC behavior and thus may be a therapeutic target, which deserves further research.

Association of Nrf2 expression and mutation with Weiss and Helsinki scores in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignant tumor. Genetic abnormalities that may represent therapeutic targets and prognostic factors in ACC remain unclear. Besides being one of the main cellular defense mechanisms that regulates antioxidant pathways for detoxifying reactive oxygen species (ROS), the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2) promotes tumor proliferation by increasing metabolic activity. In surgical specimens from 12 cases of nonmetastatic ACCs and nine cases of benign adrenocortical adenoma (ACA), we investigated gene mutation and protein expressions for Nrf2 and the preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy‐glucose positron emission tomography. Three of five ACCs with a Weiss score of 7 to 9 were Nrf2 mutants; these ACCs had higher expression of Nrf2 and higher preoperative SUVmax. The other seven ACCs had a Weiss score of 3 to 6; these seven ACCs and all the ACAs were non‐Nrf2 gene mutants. Patients with a Weiss score of 7 to 9 and Nrf2 mutant ACC had shorter overall survival. Based on Helsinki scoring, three ACCs with a Helsinki score greater than 17 had Nrf2 mutants, higher expression of Nrf2, higher preoperative SUVmax, and shorter overall survival. Our findings indicate that Nrf2 activation and the associated increase in metabolism play roles in ACC, in particular in ACC with a Weiss score of 7 to 9 and a Helsinki score of greater than 17.

Surgical resection for adrenocortical carcinoma: Current trends affecting survival.

Adrenocortical carcinoma (ACC) is associated with a poor prognosis. We reviewed the National Cancer Database (NCDB) to analyze the prognostic factors in surgically resected ACC patients and the association of surgical approaches with overall survival (OS). A retrospective NCDB (2004-2014) review of patients undergoing curative-intent surgical resection for ACC was performed. Effects of patient demographics, tumor characteristics, histopathology, and perioperative course on OS were analyzed. Log-rank statistics were used to associate clinical variables with OS. The multivariable Cox proportional hazard model included only statistically significant variables. A total of 1599 patients with ACC were included. A majority of patients were female (60.73%) and presented with a Charlson-Deyo score of zero (75.42%). A majority of the ACC cases were Grade 3 (45.69%), and almost a third (30.64%) underwent margin-positive resections. Univariate analysis demonstrated a decrease in OS associated with increasing age and comorbidities. A negative resection margin and lack of lymphovascular invasion predicted better OS. Multivariable analysis showed that age, grade, surgical resection margins, and hospital length of stay were associated with OS. Advanced age, grade, presence of lymphovascular invasion, and positive surgical margins predicted a worse overall survival for adrenocortical cancer in our analysis. Resection with negative margins improves outcomes.

Role of 18F-Fluorodeoxyglucose Positron Emission Tomography-Contrast-Enhanced Computed Tomography in Detection of Early Recurrence with Peritoneal Disease in a Case of Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is an uncommon and highly aggressive malignancy with a poor prognosis. Common sites of metastasis are lung, liver, and lymph nodes. We present a case of ACC in a 54-year-old female with an early disease recurrence of unusual hypervascular peritoneal metastatic abdominal-pelvic deposits detected on 18F-fluorodeoxyglucose positron emission tomography-contrast-enhanced computed tomography scan.

Fluoro-2-Deoxyglucose-Positron Emission Tomography/Computed Tomography in the Diagnosis and Management of Adrenocortical Carcinoma: A 10-Year Experience from a Tertiary Care Institute.

Adrenocortical carcinoma (ACC) is a rare primary malignancy of the adrenal gland. The present study was aimed to compare the performance of fluoro-2-deoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) compared to contrast-enhanced computed tomography (CECT) in diagnosis and management of ACC. A retrospective analysis of the PET-CT studies from January 2010 to October 2020 was performed. Patients with adrenal lesions suspicious of ACC and diagnosed cases of ACC who underwent PET-CT for staging, restaging, and surveillance were reanalyzed. The PET-CT parameters were compared with the clinical, biochemical, histopathological, and CECT parameters. The study included 96 scans performed in 77 patients (36 males, aged 40.4 ± 17.9 years). Of these, 55 scans were performed to diagnose and stage suspected ACC (30 of them diagnosed as ACC), 31 for restaging, and 10 scans for surveillance of ACC. PET/CT revealed metastases from an extra-adrenal primary in 5/55 patients. FDG-PET-CT had a sensitivity and specificity of 100% and 70% to diagnose ACC. Standardized uptake value-peak more than 5.4 had a sensitivity of 90.9% and specificity of 91.7% for differentiating ACC from non-ACC lesions, while tumor-to-liver ratio peak (TLRpeak) of 3.3 was most specific. PET-CT changed the staging in 23.3% of the patients with an accuracy of 100%. PET-CT changed the management plan in 25.8% of the patients during restaging with a sensitivity and specificity of 95.6% and 100%, respectively. For surveillance, CECT was as sensitive as PET-CT; however, PET-CT was more specific (100% vs. 97.9%). FDG-PET-CT performs better than CECT in the diagnosis, staging, restaging, and surveillance of ACC.

Metanephrin-producing adrenocortical carcinoma: a case report

Adrenocortical carcinoma is a rather infrequent neoplasm that mostly occurs with an autonomous secretion of steroids or steroid precursors. Previous cases have been reported with simultaneous production of metanephrines, but they were associated with intercurrent pheochromocytoma or mixed corticomedular tumors. So far, only two cases of adrenocortical carcinoma that deliver medullar hormones had been published. We herein report a singular case of a 58-year-old man with a finding of an incidental adrenal mass that demonstrated metanephrine production in the hormonal study. Consequently, initial diagnosis of pheochromocytoma was established. Microscopic examination showed an adrenal mass with marked pleomorphism and frequent mitosis. Large areas of coagulative necrosis were interspersed within the tumour. After immunohistochemistry staining there was a high expression of Ki67 (>70%) showing highly proliferative behaviour. Both cytokeratin AE1/AE3 and vimentin were positive, synaptophysin and chromogranin were negative. The surgical margins were free. Given these features, a diagnosis of metanephrin-producing adrenocortical carcinoma was done.

ASXL1 promotes adrenocortical carcinoma and is associated with chemoresistance to EDP regimen.

Adrenocortical carcinoma (ACC) is a rare but aggressive disease that lacks definitive treatment. We aim to evaluate role of ASXL1 in ACC and exploit its therapeutic merits therein. We performed in silico reproduction of datasets of the Cancer Genome Atlas (TCGA), GDSC (Genomics of Drug Sensitivity in Cancer) and Human Protein Atlas using platforms of cBioPortal, UALCAN, NET-GE, GSEA and GEPIA. Validation in ACC was performed in tissue, in vitro and in vivo using the NCI-H295R and SW-13 cells. ASXL1 was gained in over 50% of ACC cases with its mRNA overexpressed in DNA gained cases. ASXL1 overexpression was associated with recurrence and worsened prognosis in ACC. ASXL1 gain was associated with resistance to etoposide, doxorubicin and cisplatin (EDP). ASXL1 expression was positively correlated with FSCN1 expression. Targeting ASXL1 significantly impaired fitness of ACC cells, which could be in part rescued by FSCN1 overexpression. Targeting FSCN1 however could not rescue resistance to EDP induced by ASXL1 overexpression. Targeting ASXL1 sensitized ACC cells to EDP regimen but constitutive ASXL3 overexpression in SW-13 cells could induce resistance upon prolonged treatment. Functional gain of ASXL1 was common in ACC and exerted pro-tumorigenic and chemoresistance role. Targeting ASXL1 hold promise to ACC treatment.

Dermatological and endocrine elements in Carney complex (Review).

Carney complex (CΝC) is a very rare, autosomal dominant, hereditary syndrome. Seventy percent of individuals with CNC have germline inactivating or deleting mutations of the CNC1 gene [currently known as protein kinase cAMP-dependent type I regulatory subunit α (PRKAR1A), located at the 17q22-24 chromosome level], with 30% of cases presenting with phosphodiesterase gene mutations. A member of the lentiginosis family, dermatological features include: skin pigmentation, cutaneous/mucosal myxomas, usually diagnosed by the age of 20 years (neonatal presentation is exceptional, requiring a meticulous differential diagnosis). Melanocyte-derived tumors such as epithelioid blue nevi (with different levels of pigmentation) and pigmented epithelioid melanocytoma (previously 'animal-type melanoma') are often found. Myxomas, mesenchymal tumors with mostly a benign pattern, may be recurrent. Primary cutaneous melanotic schwannoma are atypical, while non-skin sites are frequent. Corticotropinomas or somatotropinomas are part of the hereditary syndrome-related pituitary adenomas (representing 5% of all). Primary pigmented nodular adrenocortical disease involves bilateral cortical hyperplasia causing Cushing syndrome (CS) at an earlier age than non-CNC cases; osteoporotic fractures seem more prevalent compare to CS of other etiologies. Typically benign, a few cases of adrenocortical carcinoma have been identified. A total of 5% of familial non-medullary thyroid cancer is syndromic, also including CNC. CNC-related thyroid frame includes: hyperthyroidism, follicular hyperplasia/adenomas, follicular carcinoma (usually aggressive, bilateral or multifocal). Large cell calcifying Sertoli cell tumors of the testes have malignant behavior in adults; in children these may induce precocious puberty. Two particular mammary tumors are found: myxoid fibroadenomas and breast myxomatosis. Cutaneous/subcutaneous lesions, pigmented or not, or any focal swelling of non-identified cause needs careful examination, since dermatological elements are among the earliest and most discernable by which to detect lesions in CNC, a systemic condition with multi-level endocrine involvement.

Beckwith–Wiedemann syndrome: Clinical, histopathological and molecular study of two Tunisian patients and review of literature

BackgroundBeckwith–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.MethodsOur 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).ResultsPatients 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.ConclusionWe 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.

Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms: a case series and literature review.

Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behaviour compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours, and guidance for surveillance and treatment strategies are lacking. To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behaviour and outcomes of malignant OANs. A retrospective clinicopathological review of 10 histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas. We reviewed all the cases of malignant OAN reported in the literature and compared to our case series. Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin-Weiss-Bisceglia criteria, LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1. In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signalling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

Computed tomography (CT) scan identified necrosis, but is it a reliable single parameter for discerning between malignant and benign adrenocortical tumors?

BackgroundAdrenocortical carcinoma is a rare malignant tumor with a poor prognosis. Discernment of adrenocortical carcinoma in an adrenal mass through imaging studies is paramount for early surgical treatment. Recently, necrosis has been proposed as a single morphological parameter for adrenocortical carcinoma diagnosis. The aim of this study was to analyze the measures of diagnostic efficiency of necrosis and the different computed tomography-scan features related to adrenocortical carcinoma diagnosis. MethodsWe conducted a case-control study of patients surgically treated for an adrenal mass with histopathological report consistent with adrenocortical carcinoma (cases) and adrenocortical adenoma (control patients) between 1987 and 2019. Radiological features on computed tomography scan were collected. Bivariate and multivariate statistical analyses were performed for the different imaging features. The measures of diagnostic efficiency for each feature were calculated. Concordance analysis between image-detected and histopathological-identified necrosis was performed. ResultsEighteen adrenocortical carcinoma and 41 adrenocortical adenomas were included. Differences between adrenocortical carcinoma and adrenocortical adenoma were found regarding heterogeneity (odds ratio 4.53, 95% confidence interval 2.3–8.9; P < .0001), tumor size ≥4 cm (odds ratio 3.5, 95% confidence interval 2.05–6.14; P < .0001), and attenuation index ≥10 Hounsfield units (odds ratio 1.9, 95% confidence interval 1.3–2.6; P = .001). Necrosis was the most important imaging feature significantly associated with adrenocortical carcinoma (odds ratio 35, 95% confidence interval 5.1–241.6; P < .0001), present in all adrenocortical carcinoma cases. After measures of diagnostic efficiency calculation, necrosis had the highest diagnostic accuracy (98%). Cohen’s kappa for concordance between image-detected and histopathological-identified necrosis was 90.4% (P < .0001). ConclusionComputed tomography scan-detected necrosis is a reliable radiological feature to discern adrenocortical carcinoma from adrenocortical adenomas.

A case of adrenocortical carcinoma in a female with rapid virilisation and mild Cushing's Syndrome

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