Influence of sex and functional status on the value of serum steroid profiling in discriminating adrenocortical carcinoma from adrenocortical adenoma.

Background: It is challenging for clinicians to distinguish adrenocortical carcinoma (ACC) from benign adrenocortical adenomas (ACA) in their early stages. This study explored the value of serum steroid profiling as a complementary biomarker for malignancy diagnosis of ACC other than diameter and explored the influence of sex and functional status. Methods: In this retrospective study, a matched cohort of patients diagnosed with either ACC or ACA based on histopathology was meticulously paired in a 1:1 ratio according to sex, age, and functional status. Eight serum steroids including 11-deoxycortisol, 11-deoxycorticosterone, progesterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and estradiol, were quantified by liquid chromatography tandem mass spectrometry. We conducted a comparative analysis of the clinical characteristics and serum steroid profiles of patients with ACC and ACA, with further subgroup analysis. Results: The study included 31 patients with ACC and 31 matched patients with ACA. Patients with ACC exhibited significantly larger tumor diameters, lower body mass index (BMI), and higher levels of 11-deoxycortisol, progesterone, and androstenedione than those with ACA. 11-deoxycortisol was the only valuable index for discriminating ACC from ACA, regardless of functional status and sex. Progesterone, DHEA, and DHEAS levels were higher in the functional ACC group than in the non-functional ACC group. Female ACC patients, especially in postmenopausal female exhibited higher levels of androstenedione than male patients. The area under the curve of tumor diameter, 11-deoxycortisol, and BMI was 0.947 (95% CI 0.889-1.000), with a sensitivity of 96.8% and specificity of 90.3%. Conclusion: Serum steroid profiling serves as a helpful discriminative marker for ACC and ACA, with 11-deoxycortisol being the most valuable marker. For other steroid hormones, consideration of sex differences and functional status is crucial.

The molecular genetics of adrenal cushing.

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/ß-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).

The efficacy of adjuvant mitotane therapy and radiotherapy following adrenalectomy in patients with adrenocortical carcinoma: A systematic review and meta-analysis.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a high recurrence rate after surgical therapy with curative intent. Adjuvant radiotherapy (RT) and mitotane therapy have been proposed as options following the adrenalectomy. However, the efficacy of adjuvant RT or mitotane therapy remains controversial. We aimed to evaluate the efficacy of adjuvant therapy in patients who underwent adrenalectomy for localised ACC. The PubMed, Scopus, and Web of Science databases were queried on March 2024 for studies evaluating adjuvant therapies in patients treated with surgery for localized ACC (PROSPERO: CRD42024512849). The endpoints of interest were overall survival (OS) and recurrence-free survival (RFS). Hazard ratios (HR) with 95% confidence intervals (95%CI) were pooled in a random-effects model meta-analysis. One randomized controlled trial (n = 91) and eleven retrospective studies (n = 4,515) were included. Adjuvant mitotane therapy was associated with improved RFS (HR: 0.63, 95%CI: 0.44-0.92, p = 0.016), while adjuvant RT did not reach conventional levels of statistical significance (HR:0.79, 95%CI:0.58-1.06, p = 0.11). Conversely, Adjuvant RT was associated with improved OS (HR:0.69, 95%CI:0.58-0.83, p<0.001), whereas adjuvant mitotane did not (HR: 0.76, 95%CI: 0.57-1.02, p = 0.07). In the subgroup analyses, adjuvant mitotane was associated with better OS (HR:0.46, 95%CI: 0.30-0.69, p < 0.001) and RFS (HR:0.56, 95%CI: 0.32-0.98, p = 0.04) in patients with negative surgical margin. Both adjuvant RT and mitotane were found to be associated with improved oncologic outcomes in patients treated with adrenalectomy for localised ACC. While adjuvant RT significantly improved OS in general population, mitotane appears as an especially promising treatment option in patients with negative surgical margin. These data can support the shared decision-making process, better understanding of the risks, benefits, and effectiveness of these therapies is still needed to guide tailored management of each individual patient.

Adrenocortical neoplasm in a 2-year-old child: Clinical approach and diagnostic imaging.

Adrenocortical tumors in children and adolescents are rare and aggressive, accounting for only 0.2% of pediatric cancers, with most cases associated with Li-Fraumeni syndrome. The most common manifestation is virilization due to androgen excess. Imaging techniques are crucial in the diagnosis and management of pediatric adrenocortical carcinoma. CT and MRI are essential for differentiating between benign and malignant lesions and assessing tumor characteristics and extent. Correlating imaging findings with clinical and histopathological data is vital for optimal diagnosis and treatment, underscoring the need for a multidisciplinary approach to managing these rare but aggressive neoplasms. This report presents the case of a previously healthy 2-year-old boy who exhibited virilization symptoms and was diagnosed with adrenocortical carcinoma.

Texture analysis can predict response to etoposide-doxorubicin-cisplatin in patients with adrenocortical carcinoma.

BACKGROUND: The adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy originating from the adrenal cortex. These patients usually undergo chemotherapy with etoposide, doxorubicin, cisplatin and mitotane (EDP-M) in case of locally advanced or metastatic ACC. Computed tomography (CT) radiomics showed to be useful in adrenal pathologies. The study aimed to analyze the association between response to EDP-M treatment and CT textural features at diagnosis in patients with locally advanced or metastatic ACCs. METHODS: We enrolled 17 patients with advanced or metastatic ACC who underwent CT before and after EDP-M therapy. The response to treatment was evaluated according to RECIST 1.1, Choi, and volumetric criteria. Based on the aforementioned criteria, the patients were classified as responders and not responders. Textural features were extracted from the biggest lesion in contrast-enhanced CT images with LifeX software. ROC curves were drawn for the variables that were significantly different (p < 0.05) between the two groups. RESULTS: Long-run high grey level emphasis (LRHGLE_GLRLM) and histogram kurtosis were significantly different between responder and not responder groups (p = 0.04) and the multivariate ROC curve combining the two features showed a very good AUC (0.900; 95%IC: 0.724-1.000) in discriminating responders from not responders. More heterogeneous tissue texture of initial staging CT in locally advanced or metastatic ACC could predict the positive response to EDP-M treatment. CONCLUSIONS: Adrenal texture is able to predict the response to EDP-M therapy in patients with advanced ACC.

Treatment Outcomes in Patients with Recurrent Adrenocortical Carcinoma.

BACKGROUND: While numerous studies have explored treatment outcomes for the overall ACC patient cohort, data on the subpopulation of patients with recurrent disease are limited. Therefore, the aim of this study was to assess treatment outcomes in patients with recurrent ACC. METHODS: In this retrospective study, we included 18 patients median age 49 years (42-62); 67% female) diagnosed with recurrent ENSAT stage I-III ACC who underwent either R0 (n = 16) or Rx (n = 2) surgical resection of the tumor. RESULTS: The median time from the initial surgery to ACC recurrence was 29 months (IQR 18-50). Seven patients (39%) manifested local recurrence, while 11 patients (61%) developed distant metastases. The median follow-up duration after tumor recurrence was 32 months (IQR 25-53). Regarding the treatment of ACC recurrence, 10 patients underwent a second surgery either as an alone procedure (n = 4), or in combination with mitotane (n = 4), mitotane and chemotherapy (n = 1), or mitotane combined with radiotherapy (n = 1). The remaining patients received treatment involving chemotherapy±mitotane (n = 4) and locoregional therapy ±chemotherapy (n = 3). One patient chose not to proceed with further management and follow-up. The median PFS was 17 (95% CI 8-26) months while the median OS was not reached. In the multivariate model, increased mortality was associated with advanced age (p = 0.04) and a shorter interval to ACC recurrence (p = 0.03). CONCLUSION: A significant proportion of patients with ACC recurrence experience disease progression or second recurrence, despite all treatment efforts. Nevertheless, by integrating diverse treatment modalities, many patients have the potential to attain long-term survival.

Adverse Events of Adjuvant Mitotane Treatment for Adrenocortical Carcinoma.

BACKGROUND: Mitotane is the cornerstone of adjuvant adrenocortical cancer (ACC) treatment. However, its use is burdened with frequent adverse events. METHODS: A retrospective analysis of adverse events was performed in 26 ACC patients adjuvantly treated with mitotane. RESULTS: Mitotane toxicity was present in all patients (100%). Two (7.7%) patients developed 1-3 adverse events, 15 (57.7%) experienced 4-6 adverse events and 9 (34.6%) patients had more than 6 adverse events. Two (7.7%) patients discontinued mitotane due to adverse events. CONCLUSION: Careful monitoring and timely management are essential for ensuring mitotane treatment adherence and maximizing its benefits.

Serum steroid profiling in the diagnosis of adrenocortical carcinoma: a prospective cohort study.

CONTEXT: Guidelines suggest performing urine steroid profiling in patients with indeterminate adrenal tumors to make a noninvasive diagnosis of adrenocortical carcinoma (ACC). However, urine steroid profiling is not widely available. OBJECTIVE: To determine the accuracy of clinically available serum 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone in diagnosing ACC. METHODS: We conducted a prospective single-center cohort study of patients with adrenal masses evaluated between 2015-2023. Serum was analyzed by liquid chromatography-mass spectrometry for 17OH-pregnenolone, 17OH-progesterone, 11-deoxycortisol. Reference standard for adrenal mass included histopathology, imaging characteristics, imaging follow up of 2 years, or clinical follow up of 5 years. Localized Generalized Matrix Learning Vector Quantization (LGMLVQ) analysis was used to develop serum steroid score and assessed with area under receiver operating curve (AUROC). RESULTS: Of 263 patients with adrenal masses, 44 (16.7%) were diagnosed with ACC, 161 (61%) with adrenocortical adenomas (ACAs), 27 (10%) with other adrenal malignancies, and 31 (12%) with other. Hounsfield unit (HU) ≥ 20 was demonstrated in all ACCs, in all but one other adrenal malignancy, and in 58 (31%) ACAs. All 3 steroids were higher in patients with ACCs vs non-ACCs, including when comparing ACCs with functioning ACAs, and with ACAs with HU ≥ 20 (P<0.0001 for all). LGMLVQ analysis yielded a serum steroid score that discriminated between ACC and non-ACC groups with a mean threshold fixed AUROC of 0.823. CONCLUSIONS: We showed that measurements of 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone could be valuable in diagnosing ACC. After appropriate validation, serum steroid score could be integrated in clinical practice.

Etoposide, cisplatin, and sintilimab combined with anlotinib in successful treatment of adrenocortical carcinoma with lung metastasis: a case report.

Background: Adrenocortical carcinoma (ACC) is a rare malignant tumor that occurs in the adrenal cortex. It has a high degree of malignancy and comparatively poor overall prognosis. Surgery is the standard curative therapy for localized ACC patients. The combination regimen of etoposide, doxorubicin, cisplatin (EDP) plus mitotane has been considered as the standardized chemotherapy regimen for advanced ACC. However, new effective regimens are emerging for specific conditions in metastatic ACC. Case presentation: We report a case of a 66-year-old man diagnosed with metastatic ACC who had a large left adrenal mass (110 mm × 87 mm) and multiple metastases in both lungs. The patient was treated with EP and sintilimab for six cycles; anlotinib was introduced after the third cycle. Follow-ups after the second to fourth cycles found significantly reduced lung metastases with all imaging examinations indicating partial response (PR) status. The patient received maintenance therapy thereafter with sintilimab plus anlotinib. Until recently, the patient's lung metastases and the left adrenal gland area mass (39mm × 29mm) have disappeared, and no disease progression has been observed. The progression-free survival of this patient has been extended to approximately 31 months, in sharp contrast to a median survival time of 12 months for majority of advanced ACC. The main adverse events during treatment were appetite loss and grade I myelosuppression and revealed only grade I hypertension and grade I hypothyroidism. Conclusion: This case highlights the remarkable response of our patient's ACC to treatment with a novel combination of EP and sintilimab combined with anlotinib. Our findings suggest a safe and more effective combination therapeutic option for patients with adrenocortical carcinoma.

A puzzling malignant adrenal tumor.

A previously healthy 49-year-old male presented with abdominal pain, constitutional syndrome, paroxysmal palpitations and diaphoresis. Full-body CT scan showed a large malignant adrenal mass with abdominal lymph node and pulmonary metastasis. Biochemical studies revealed hypersecretion of catecholamines, cortisol, sexual steroids and steroid precursors; ACTH was not suppressed, and chromogranin A was negative. 18F-fluorodeoxyglucose PET/CT showed intense tracer uptake in the adrenal mass and abdominal lymph nodes. He was placed under adrenergic blockade and offered cytoreductive surgery, but his evolution was unfavorable with rapid clinical deterioration due to compressive abdominal symptoms, uncontrolled pain, peripheral oedema, cachexia and severe dilated cardiomyopathy. 123I-metaiodobenzylguanidine scintigraphy was negative. Poor clinical status precluded any surgical or systemic treatments. A biopsy of the adrenal mass suggested adrenocortical carcinoma. Two weeks later he developed recurrent level 3 non-insulin mediated hypoglycemias, with suppressed levels of insulin, C-peptide, IGF-1 and IGF-BP3. He responded poorly to palliative measures and died within a week, four months after the initial diagnosis. We present a puzzling case of an aggressive stage IV adrenal malignancy with bizarre secretory profile. Although we could not obtain a surgical specimen, combined available data suggested adrenocortical carcinoma. The pathophysiology is uncertain, and we explored exceedingly rare scenarios, including adrenocortical carcinoma masquerading as pseudo-pheochromocytoma; synchronous adrenocortical carcinoma and pheochromocytoma; adrenal mixed corticomedullary tumor; and ACTH-producing pheochromocytoma. The presence of ectopic ACTH-dependent hypercortisolism, discordant plasma and urinary metanephrine levels and IGF-2 mediated hypoglycemias were also quite perplexing. To our knowledge, this is the first report of a malignant adrenal tumor co-secreting steroid hormones with ACTH-dependent hypercortisolism, catecholamines and IGF-2. We faced obvious diagnostic and therapeutic challenges and encourage future studies to explore the complex interactions between cortical and chromaffin cells of the adrenal gland, that may have bidirectionally contributed to this patient's condition.

The Modified S-GRAS Scoring System for Prognosis in Korean with Adrenocortical Carcinoma.

Background: Adrenocortical carcinomas (ACCs) are rare tumors with aggressive but varied prognosis. Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score, based on clinical and pathological factors, was found to best stratify the prognosis of European ACC patients. This study assessed the prognostic performance of modified S-GRAS (mS-GRAS) scores including modified grade (mG) by integrating mitotic counts into the Ki67 index (original grade), in Korean ACC patients. Methods: Patients who underwent surgery for ACC between January 1996 and December 2022 at three medical centers in Korea were retrospectively analyzed. mS-GRAS scores were calculated based on tumor stage, mG (Ki67 index or mitotic counts), resection status, age, and symptoms. Patients were divided into four groups (0-1, 2-3, 4-5, and 6-9 points) based on total mS-GRAS score. The associations of each variable and mS-GRAS score with recurrence and survival were evaluated using Cox regression analysis, Harrell's concordance index (C-index), and the Kaplan-Meier method. Results: Data on mS-GRAS components were available for 114 of the 153 patients who underwent surgery for ACC. These 114 patients had recurrence and death rates of 61.4% and 48.2%, respectively. mS-GRAS score was a significantly better predictor of recurrence (C-index=0.829) and death (C-index=0.747) than each component (P<0.05), except for resection status. mS-GRAS scores correlated with shorter progression-free survival (P=8.34E-24) and overall survival (P=2.72E-13). Conclusion: mS-GRAS scores showed better prognostic performance than tumor stage and grade in Asian patients who underwent surgery for ACC.

Powder Self-Emulsifying Drug Delivery System for Mitotane: In Vitro and In Vivo Evaluation.

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing's syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients.

Polish diagnostic and therapeutic recommendations for adrenocortical carcinoma.

Advances in the diagnosis and treatment of adrenocortical carcinoma (ACC), along with the development of new therapeutic and diagnostic methods, have prompted a team of experts to formulate the first Polish guidelines for managing ACC. This article presents the diagnostic and therapeutic recommendations resulting from the discussion of specialists from various medical specialities, who participated in a series of online meetings aimed at developing consistent and effective recommendations under the National Oncology Strategy. These guidelines aim to optimise ACC treatment in Poland through coordinated efforts of multidisciplinary specialist teams, ensuring an effective and modern approach.

Ruptured triple hormone-secreting adrenal cortical carcinoma with hyperaldosteronism, hypercortisolism, and elevated normetanephrine: a case report.

We report a case of a ruptured triple hormone-secreting adrenal mass with hyperaldosteronism, hypercortisolism, and elevated normetanephrine levels, diagnosed as adrenal cortical carcinoma (ACC) by histology. A 53-year-old male patient who initially presented with abdominal pain was referred to our hospital for angiocoagulation of an adrenal mass rupture. Abdominal computed tomography revealed a heterogeneous 19×11×15 cm right adrenal mass with invasion into the right lobe of the liver, inferior vena cava, retrocaval lymph nodes, and aortocaval lymph nodes. Angiocoagulation was performed. Laboratory evaluation revealed excess cortisol via a positive 1-mg overnight dexamethasone suppression test, primary hyperaldosteronism via a positive saline infusion test, and plasma normetanephrine levels three times higher than normal. An adrenal mass biopsy was performed for pathological confirmation to commence palliative chemotherapy because surgical management was not deemed appropriate considering the extent of the tumor. Pathological examination revealed stage T4N1M1 ACC. The patient started the first cycle of adjuvant mitotane therapy along with adjuvant treatment with doxorubicin, cisplatin, and etoposide, and was discharged. Clinical cases of dual cortisol- and aldosterone-secreting ACCs or ACCs presenting as pheochromocytomas have occasionally been reported; however, both are rare. Moreover, to the best of our knowledge, a triple hormone-secreting ACC has not yet been reported. Here, we report a rare case and its management. This case report underscores the necessity of performing comprehensive clinical and biochemical hormone evaluations in patients with adrenal masses because ACC can present with multiple hormone elevations.

Loco-regional recurrence of adrenocortical carcinoma: A case report.

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a high recurrence rate. Approximately half of the patients are asymptomatic, while others experience symptoms due to the tumor's size or hormone secretion. Ro resection if possible is the best option for treatment of primary as well as locoregional recurrent ACC. CASE PRESENTATION: A 20-year-old female who previously underwent open left adrenalectomy for Stage III ACC presented with complaints of heaviness and vague discomfort in the left upper abdomen. Current hormonal assays were normal. Imaging revealed a lesion in the spleen suggestive of recurrence. She underwent elective surgery involving en bloc resection of the spleen, diaphragm, and associated structures. Postoperative recovery was uneventful, histopathology confirmed recurrence and subsequent PET-CT showed no recurrence. She is currently on mitotane and remains symptom-free with no signs of recurrence after initial surgery. CLINICAL DISCUSSION: Complete resection (Ro) if possible, for recurrent and metastatic disease has been linked to long-term survival and offers significant palliative benefits, particularly in cases involving symptomatic steroid production. CONCLUSION: ACC has a high frequency of local recurrence therefore management of recurrence should be considered from the initial diagnosis. Ro resection of recurrence is the best potential treatment. Follow-up protocols and improving integration between surgical, oncological, and supportive care departments are crucial for overcoming healthcare challenges in Nepal.

Differences in life expectancy of adrenocortical carcinoma patients vs. age­ and sex-matched population controls.

PURPOSE: To quantify to what extent the 5-year overall survival (OS) of adrenocortical carcinoma (ACC) patients differs from age- and sex-matched population-based controls, especially when stage is considered. METHODS: We relied on the Surveillance, Epidemiology, and End Results database (2004-2020) to identify newly diagnosed (2004-2014) ACC patients. Subsequently, we compared OS between ACC patients relative to simulated age- and sex-matched controls (Monte Carlo simulation), according to Social Security Administration Life Tables (2004-2020). RESULTS: Of all 742 ACC patients, 301 (41%) harbored localized stage, 173 (23%) locally advanced stage, and 268 (36%) metastatic stage. At 5-years follow-up, ACC patients' OS was 33%. After stratification for stage, the 5-years OS was 55 vs. 31 vs. 8% in localized, locally advanced, and metastatic stages, respectively. Conversely, after Monte Carlo simulation of age- and sex-matched controls, OS at five-years was 93% in the entire simulated cohort vs. 94% in the simulated localized cohort vs. 92 and 92% in locally advanced and metastatic stage, respectively. The resulting differences in OS between ACC patients and age- and sex-matched population-based controls were 60 vs. 39 vs. 61 vs. 84% respectively in the overall cohort vs. localized vs. locally advanced vs. metastatic stage. CONCLUSION: The most pronounced life expectancy detriment (84%) was recorded in metastatic ACC followed by locally advanced ACC patients (61%). Unfortunately, even in patients with localized ACC, life expectancy was 39% lower than that of the general population. Therefore, regardless of stage, ACC diagnosis results in a very pronounced detriment in life expectancy relative to the general population.

Development and validation of a liquid chromatography coupled to a diode array detector (LC-DAD) method for measuring mitotane (DDD) in plasma samples.

INTRODUCTION: Mitotane (o,p'-DDD) is the drug of choice for Adrenocortical Carcinomas (ACC) and its measurement in plasma is essential to control drug administration. OBJECTIVE: To develop and validate a simple, reliable and straightforward method for mitotane determination in plasma samples. METHOD: Drug-free plasma samples were collected in potassium-ethylenediamine tetraacetate (K-EDTA) tubes and spiked with 1.0, 2.5, 10.0, 25.0 and 50.0 µg/mL of mitotane (DDD). The p,p'-DDD was used as an Internal Standard (IS) and was added at 25.0 µg/mL concentration to all samples, standards and controls. Samples were submitted to protein precipitation with acetonitrile and then centrifuged. 50 uL of the supernatant was injected into an HPLC system coupled to a Diode Array Detector (DAD). DDD and IS were detected at 230 nm in a 12 min isocratic mode with a solvent mixture of 60 % acetonitrile and 40 % formic acid in water with 0.1 % pump mixed, at 0.6 mL/min flow rate, in a reversed-phase (C18) chromatographic column kept at 28°C. The sensitivity, selectivity, precision, presence of carry-over, recovery and matrix-effect, linearity, and method accuracy were evaluated. RESULTS: The present study's method resulted in a symmetrical peak shape and good baseline resolution for DDD (mitotane) and 4,4'-DDD (internal standard) with retention times of 6.0 min, 6.4 mim, respectively, with resolutions higher than 1.0. Endogenous plasma compounds did not interfere with the evaluated peaks when blank plasma and spiked plasma with standards were compared. Linearity was assessed over the range of 1.00-50.00 µg/mL for mitotane (R2 > 0.9987 and a 97.80 %‒105.50 % of extraction efficiency). Analytical sensitivity was 0.98 µg/mL. Functional sensitivity (LOQ) was 1.00 µg/L, intra-assay and inter-assay coefficient of variations were less than 9.98 %, and carry-over was not observed for this method. Recovery ranged from 98.00 % to 117.00 %, linearity ranged from 95.00 % to 119.00 %, and high accuracy of 89.40 % to 105.90 % with no matrix effects or interference was observed for mitotane measurements. Patients' sample results were compared with previous measurements by the GC-MS method with a high correlation (r = 0.88 and bias = -10.20 %). CONCLUSION: DDD determination in plasma samples by the developed and validated method is simple, robust, efficient, and sensitive for therapeutic drug monitoring and dose management to achieve a therapeutic index of mitotane in patients with adrenocortical cancer.

Adrenocortical carcinoma: selective internal radiation therapy and liver metastases.

Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years' PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation. Significance statement: Adrenocortical carcinoma (ACC) is a rare and aggressive tumour with limited treatments. Once metastatic disease develops, existing standard-of-care treatments offer a dismal overall survival, alongside marked toxicities. Selective internal radiation therapy (SIRT) may represent a new intervention in the treatment paradigm for liver-limited, metastatic ACC. Here, we present the case of a patient treated with multiple rounds of SIRT for relapsed, liver-limited ACC, prolonging survival by several years. Recurrent SIRT led to maintained liver function and no toxicities. Little evidence outlines its use in ACC but further study is certainly warranted to ascertain the value of SIRT, considering the limited treatment landscape that currently exists.

Papillary Thyroid Carcinoma, Cushing Disease, and Adrenocortical Carcinoma in a Patient with Li-Fraumeni Syndrome.

Background/Objective: Li-Fraumeni syndrome (LFS) is an inherited sequence variant in TP53 characterized by the early onset of various core malignancies including adrenocortical carcinoma (ACC), sarcomas, breast cancer, leukemias, and central nervous system tumors. We present a case of a patient with LFS who developed endocrine neoplasms not classically seen in LFS in addition to developing ACC. Case Report: A 26-year-old nonbinary individual assigned female at birth with a history of LFS complicated by osteosarcoma of the jaw was incidentally found to have thyroid and sellar masses on surveillance magnetic resonance imaging. Fine-needle aspiration of thyroid mass confirmed papillary thyroid carcinoma, and the patient underwent total thyroidectomy. Pituitary workup was notable for laboratory test results consistent with adrenocorticotropic hormone-dependent hypercortisolism; the patient underwent resection of the pituitary lesion. The patient was subsequently noted on abdominal imaging to have a new left adrenal mass; they underwent left adrenalectomy with pathology consistent with ACC. Discussion: There is limited literature on the relationship between LFS and thyroid and pituitary neoplasms. Genetic testing has suggested that TP53 sequence variants may play a role in tumorigenesis in thyroid and pituitary neoplasms; however, most of the current literature is based on evidence of somatic rather than germline sequence variants. Conclusion: This case highlights a patient with LFS with neoplasia of multiple endocrine organs including ACC, which is a classic finding, as well as papillary thyroid carcinoma and Cushing disease. Further investigation may be necessary to assess if patients with LFS are at a higher risk of various endocrine neoplasms in addition to the core malignancies classically described because this could affect future screening protocols.

LncRNA ZFHX4-AS1 as a novel biomarker in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignant tumor. Currently, there is a lack of reliable prognostic markers in clinical practice. Extensive research has shown that long non-coding RNA (lncRNA) are critical factors in the initiation and progression of cancer, closely associated with early diagnosis and prognosis. Previous studies have identified that ZFHX4 antisense RNA 1 (ZFHX4-AS1) is aberrantly expressed in various cancers and is associated with poor outcomes. This study investigates whether ZFHX4-AS1 affects the prognosis of ACC patients and, if so, the potential mechanisms involved. Methods: In this study, utilizing four multi-center cohorts from The Cancer Genome Atlas (TCGA) program and Gene Expression Omnibus (GEO), we validated the prognostic capability of ZFHX4-AS1 in ACC patients through Kaplan-Meier survival analysis, cox regression models, and nomograms. Then, we explored the biological functions of ZFHX4-AS1 using gene set enrichment analysis (GSEA), competing endogenous RNA (ceRNA) networks, and analyses of somatic mutations and copy number variation (CNV). Finally, in vitro experiments were conducted to further validate the impact of ZFHX4-AS1 on proliferation and migration capabilities of ACC cell lines. Results: Survival analysis indicated that patients in the high ZFHX4-AS1 expression group of ACC had worse prognosis. Cox regression analyses suggested that ZFHX4-AS1 levels were independent risk factors for prognosis. Subsequently, we constructed nomograms based on clinical features and ZFHX4-AS1 levels, demonstrating good predictive performance under the time-dependent receiver operating characteristic (ROC) curve. Analysis based on somatic mutations and CNV revealed that CTNNB1 and 9p21.3-Del drove the expression of ZFHX4-AS1. Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays confirmed that knockdown of ZFHX4-AS1 inhibited proliferation and migration of ACC cells. Conclusions: This study demonstrates that ZFHX4-AS1 has a reliable predictive value for the prognosis of ACC patients and is a promising biomarker.