[The algorithm for morphological assessment of malignant potential of adrenocortical tumors using mathematical modeling method]. / Algoritm morfologicheskoi otsenki zlokachestvennogo potentsiala adrenokortikal'nykh opukholei s ispol'zovaniem metoda matematicheskogo modelirovaniya.

OBJECTIVE: To develop the mathematical model with high sensitivity and specificity to assess the malignant potential of adrenal cortical tumors, which can be used to diagnose adrenocortical carcinoma (ACC) in adults. MATERIAL AND METHODS: Pathomorphological examination of surgical and consultative material of adrenocortical neoplasms was carried out. All cases were verified according to the WHO Classification of adrenal gland tumors (5th ed., 2022), the tumor's histogenesis was confirmed by immunohistochemical examination. Statistical analysis of the histological and immunohistochemical factors in terms of their value in relation to the diagnosis of ACC was carried out on Python 3.1 in the Google Colab environment. ROC analysis was used to identify critical values of predictors. The cut-off point was selected according to the Youden`s index. Logistic regression analysis using l1-regularisation was performed. To validate the model, the initial sample was divided into training and test groups in the ratio of 9:1, respectively. RESULTS: The study included 143 patients divided into training (128 patients) and test (15 patients) samples. A prognostic algorithm was developed, which represent a diagnostically significant set of indicators of the currently used Weiss scale. The diagnosis is carried out in 3 stages. This mathematical model showed 100% accuracy (95% CI: 96-100%) on the training and test samples. CONCLUSION: The developed algorithm could solve the problem of subjectivity and complexity in the interpretation of some of the criteria of current diagnostic algorithms. The new model is unique in that, unlike others, it allows verification of all morphological variants of ACC.

Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group.

OBJECTIVE: Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. DESIGN: Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. METHODS: We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). RESULTS: We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. CONCLUSION: In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.

[Multifactorial assessment of prognostic features of adrenocortical cancer]. / Mul'tifaktornaya otsenka prognosticheskikh osobennostei adrenokortikal'nogo raka.

OBJECTIVE: To determine the predictors of the aggressive course of adrenocortical cancer (ACC). ACC is a rare malignant neoplasm of the adrenal cortex with a variable prognosis. At present, predicting the course of the disease and clinical outcome in patients presents significant difficulties, since many aspects of the treatment of ACC have not been studied or require clarification. In particular, the prognostic value of markers that are used in clinical practice has not been fully determined. MATERIAL AND METHODS: Histological and immunohistochemical studies of the surgical material of adrenal neoplasms were performed. The study included 73 patients with a histologically confirmed diagnosis of ACC: 51 (69.9%) women and 22 (30.1%) men aged 17 to 82 years. Cox regression model was used for survival analysis. Statistically significant factors (p<0.05) according to the results of independent regression analysis were included in the Kaplan-Meier analysis followed by pairwise comparison using the log-rank test. RESULTS: An increased risk of recurrence is associated with the presence of pathological mitoses and excessive secretion of aldosterone, death - with stage IV according to the classification of the European Network for the Study of Adrenal Tumors (ENSAT), relapse and death - the value of mitotic activity more than 20, the Ki-67 index more than 12, the classic variant. Mitotic activity and hormonal activity were independent predictors of recurrence-free survival, mitotic activity and ENSAT stage were independent predictors of overall survival. CONCLUSIONS: In the present work, potential predictors of the course of ACC are identified, which are available for use in routine practice. Based on the totality of clinical, morphological, immunohistochemical data used in the diagnosis of ACC, a conception of the patient's survival can be obtained.

Liquid biopsy for the assessment of adrenal cancer heterogeneity: where do we stand?

Almost 10 years have passed since the first attempts of liquid biopsy aimed at the characterisation of tumor cells present in the bloodstream from a regular sample of peripheral blood were performed. Liquid biopsy has been used to characterise tumor heterogeneity in various types of solid tumors including adrenocortical carcinoma. The development of molecular biology, genetics, and methodological advances such as digital PCR and next-generation sequencing allowed us to use besides circulating tumor cells a variety of circulating cell-free nucleic acids, DNAs, RNAs and microRNAs secreted by tumors into blood and other body fluids as specific molecular markers. These markers are used for diagnosis, to check tumor development, selecting efficient therapies, therapy monitoring and even possess prognostic power. In adrenocortical carcinoma, there are some studies reporting analysis of circulating tumor cells, circulating cell free DNA and microRNAs for assessing tumor heterogeneity. Among microRNAs, hsa-miR-483-5p seems to be the most important player. Combined with other microRNAs like hsa-miR-195, their expression correlates with recurrence-free survival. Most studies support the applicability of liquid biopsy for assessing temporal tumor heterogeneity (i.e. tumor progression) in adrenocortical cancer. In this mini-review, the available findings of liquid biopsy for assessing tumor heterogeneity in adrenocortical cancer are presented.

Disparate Practice Patterns and Survival Outcomes: The Impact of Centralization of Cancer Care for Adrenocortical Carcinoma in the United States.

PURPOSE: Adrenocortical carcinoma is a rare but aggressive malignancy. While centralization of care to referral centers improves outcomes across common urological malignancies, there exists a paucity of data for low-incidence cancers. We sought to evaluate differences in practice patterns and overall survival in patients with adrenocortical carcinoma across types of treating facilities. MATERIALS AND METHODS: We identified all patients diagnosed with adrenocortical carcinoma from 2004-2016 in the National Cancer Database. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox regression analysis was used to investigate independent predictors of overall survival. The chi-square test was used to analyze differences in practice patterns. RESULTS: We identified 2,886 patients with adrenocortical carcinoma. Median overall survival was 21.8 months (95% CI 19.8-23.8). Academic centers had improved overall survival versus community centers on unadjusted Kaplan-Meier analysis (p <0.05) and had higher rates of adrenalectomy or radical en bloc resection (p <0.001), performed more open surgery (p <0.001), administered more systemic therapy (p <0.001) and had lower rates of positive surgical margins (p=0.03). On multivariable analysis, controlling for treatment modality, academic centers were associated with significantly decreased risk of death (HR 0.779, 95% CI 0.631-0.963, p=0.021). CONCLUSIONS: Treatment of adrenocortical carcinoma at an academic center is associated with improved overall survival compared to community programs. There are significant differences in practice patterns, including more aggressive surgical treatment at academic facilities, but the survival benefit persists on multivariable analysis controlling for treatment modality. Further studies are needed to identify the most important predictors of survival in this at-risk population.

Assessment and management of advanced adrenocortical carcinoma using a precision oncology care model.

Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)-based genomic and other '-omic' profiling to guide the precision medicine approach and personalized use of targeted and novel therapies.

Preoperative workup in the assessment of adrenal incidentalomas: outcome from 282 consecutive laparoscopic adrenalectomies.

BACKGROUND: To confirm the efficacy of preoperative workup, the authors analyse the results of a multicentre study in a surgical series of patients diagnosed with an adrenal incidentaloma. METHODS: The retrospective review of a prospectively collected database was conducted. The data was obtained by six surgical units operating in the Campania Region, Italy. Five-hundred and six (506) adrenalectomies performed between 1993 and 2011 on 498 patients were analysed. Final histology in patients with a preoperative diagnosis of incidentaloma and studied according to guidelines (230/282 patients group A) was compared with final histology coming from patients presenting the same preoperative diagnosis but studied not according to guidelines (52/282 patients group B). RESULTS: In group A preoperative diagnosis was confirmed at final histology in 76/81 (93.8%) cases of subclinical functioning lesions presenting as an incidentaloma. The preoperative detection of pheochromocytoma and primary adrenocortical cancer (ACC) reached 91.6% and 84.6% respectively. In group B conversion rate to open surgery was higher than in group A (p = 0.02). One pheochromocytoma was missed at preoperative diagnosis whereas one ACC smaller than 4 centimetres (cm) and coming from an incidental lesion was discovered. In both groups a significant association between increasing dimensions of incidentaloma and cancer has been observed (p = 0.001). CONCLUSIONS: This surgical series confirm the high efficacy of suggested guidelines. A significant preoperative detection rate of adrenal lesions presenting as incidentaloma is observed. The unnecessary number of adrenalectomies performed in understudied patients, causing higher morbidity, was not associated to a higher detection rate of primary adrenocortical cancer.

A cost-effectiveness analysis of adrenalectomy for nonfunctional adrenal incidentalomas: is there a size threshold for resection?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, but aggressive, malignancy. Current American Association of Clinical Endocrinologists (AACE)/American Association of Endocrine Surgeons (AAES) guidelines recommend resection of nonfunctional adrenal neoplasms ≥ 4 cm. This study evaluates the cost-effectiveness of this approach. METHODS: A decision tree was constructed for patients with a nonfunctional, 4-cm adrenal incidentaloma with no radiographic suspicion for ACC. Patients were randomized to adrenalectomy, surveillance per AACE/AAES guidelines, or no follow-up ("sign-off"). Incremental cost-effectiveness ratio (ICER) includes health care costs, including missed ACC. ICER (dollar/life-year-saved [LYS]) was determined from the societal perspective. Sensitivity analyses were performed. RESULTS: In the base-case analysis, assuming a 2.0% probability of ACC for a 4-cm tumor, surgery was more cost-effective than surveillance (ICER $25,843/LYS). Both surgery and surveillance were incrementally more cost-effective than sign-off ($35/LYS and $8/LYS, respectively). Sensitivity analysis demonstrated that the model was sensitive to patient age, tumor size, probability of ACC, mortality of ACC, and cost of hospitalization. The results of the model were stable across different cost and complications related to adrenalectomy, regardless of operative approach. CONCLUSION: In our model, adrenalectomy was cost-effective for neoplasms >4 cm and in patients <65 years, primarily owing to the aggressiveness of ACC. Current AACE/AAES guideline recommendations for the resection of adrenal incidentalomas ≥ 4 cm seem to be cost-effective.

Deficits in the management of patients with adrenocortical carcinoma in Germany.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. METHODS: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical follow-up. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). RESULTS: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21% of them underwent no hormonal evaluation before surgery, and 59% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. CONCLUSION: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.

[Weiss system: a still in-use diagnostic tool for the assessment of adrenocortical malignancy]. / Le système de Weiss: un outil toujours d'actualité pour le diagnostic de malignité des tumeurs de la corticosurrenale.

Adrenocortical carcinomas are rare tumors. In the absence of the gold standard that constitutes metastases, local invasion or recurrence, the diagnosis of malignancy may represent a great challenge for both clinicians and pathologists. Several multiparametric systems have been developed to assess this malignancy. Among them, the Weiss system, established in 1984 and based on nine microscopic criteria, appears to be the most employed because of its simplicity and reliability. The presence of three and more criteria is in favor of malignancy. However, the application of such system is not devoid of difficulties and subjectivity. A more precise definition of the different microscopic criteria and the proposition of a modified Weiss system based on the most reliable criteria could help. Besides, the Weiss system is of limited value for the diagnosis of malignancy in oxyphil tumors and children tumors of the adrenal cortex.

Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors.

OBJECTIVES: To evaluate the utility of Ki-67 immunohistochemical analysis in the differential diagnosis between benign and malignant adrenocortical neoplasms. METHODS: Tissue specimens were obtained from 37 patients referred to our institute from 1990 to 1999. The indications for adrenalectomy were adrenal-dependent Cushing syndrome (n = 9), hyperandrogenism (n = 1), mineralocorticoid excess (n = 8), and nonfunctioning adrenal masses (n = 19). The histologic diagnosis was cortical adenoma in 26 of 37 patients and cortical carcinoma in the remainder. Normal adrenal glands were obtained from subjects who underwent radical nephrectomy because of initial renal carcinoma. Immunohistochemical analysis was performed using the monoclonal antibody anti-Ki-67 (clone MIB-1). The Ki-67 labeling index was expressed as the number of positive cells per 1000 cells.Results. The average Ki-67 expression was 2.0 per thousand +/- 1.2 per thousand (SD) in normal adrenal glands, 11.3 per thousand +/- 16.0 per thousand in adenomas, and 185.8 per thousand +/- 60.3 per thousand in carcinomas (P <0.0001). A threshold value of the Ki-67 labeling index between 70 per thousand and 90 per thousand reliably separated adenoma from carcinoma. A significant inverse correlation was found between Ki-67 expression and overall survival in patients with adrenal carcinoma (r = -0.74, P = 0.009). CONCLUSIONS: Immunohistochemical assessment of the nuclear antigen Ki-67 can be useful in the differential diagnosis between adrenocortical adenoma and carcinoma. High levels of Ki-67 seem to indicate patients with adrenocortical cancer with a worse prognosis.

Comparison of two algorithms and their associated charges when evaluating adrenal masses in patients with malignancies.

OBJECTIVE: This study was performed to compare two proposed algorithms used when evaluating an adrenal mass discovered during staging evaluation of a patient with a known malignancy. Such evaluation was meant to lead to determination of the relative charges associated with each algorithm. SUBJECTS AND METHODS: Fifty-four patients with known malignancies who required evaluation of an adrenal mass underwent both chemical shift imaging (CSI) and CT-guided for CSI. The hospital charges incurred for each procedure and any associated complications were normalized using national relative-value scale charges and conversion factors. A decision analysis was performed to compare the relative charges that would have been incurred if adrenal MR imaging had been performed in all patients, followed by CT-guided biopsy only in those patients with MR findings not diagnostic of adrenocortical adenoma, and the relative charges incurred if only CT-guided adrenal biopsy had been performed in every patient. RESULTS: Twenty-three (43%) of 54 adrenal masses were shown to be metastases by CT-guided biopsy. The sensitivity and specificity of CSI for the diagnosis of adrenocortical adenoma were 94% and 100%, respectively. The charges incurred by performing MR imaging as the initial examination with subsequent CT-guided biopsy only in those patients with CSI findings not diagnostic of adenoma would have been similar to those incurred by first performing CT-guided adrenal biopsy in every patient. CONCLUSION: CSI is an accurate, noninvasive technique for evaluating adrenal masses in patients with cancer. If CT-guided biopsy is used only when CSI is not diagnostic of adrenocortical adenoma, the associated charges would be virtually the same as when CT-guided biopsy is performed as the first test in every patient. Moreover, biopsies could have been avoided in 54% of these patients.

Scintigraphic assessment of therapeutic success in aldosteronomas treated by transcatheter arterial embolization using absolute ethanol.

UNLABELLED: Adrenocortical scintigraphy was examined as an indicator of therapeutic success in aldosteronomas treated by transcatheter arterial embolization (TAE) with absolute ethanol (AE). METHODS: Adrenocortical scintigraphy was performed 7 days after intravenous injection of 37 MBq 131I-6-beta-iodomethyl-19-norcholesterol before and after TAE. Complete or incomplete therapeutic success was determined by periodic measurements of the levels of plasma aldosterone and correlated with the scintigraphic results. RESULTS: The aldosteronoma was visualized as a hot nodule in nine patients and a warm nodule in one patient before TAE. Scintigraphy showed a hot, residual hot or warm nodule on seven occasions (six occasions after the first TAE and one occasion after the second TAE) when the techniques were incompletely successful and disappearance on seven occasions when success was achieved (three occasions after the first TAE and one occasion after the second TAE). Of the seven occasions when TAE was unsuccessful, four patients received the second or third TAE to result in complete destruction of the aldosteronoma; three patients underwent unilateral adrenalectomy. CONCLUSION: Adrenocortical scintigraphy can correctly predict the effect of TAE on aldosteronomas and is a valuable indicator for decisions on the necessity of repeated TAE or adrenalectomy.

An imaging algorithm for the differential diagnosis of adrenal adenomas and metastases.

OBJECTIVE: The purpose of this study was to develop an algorithm using CT and chemical-shift MR imaging for the characterization of adrenal masses in patients with a primary cancer and no other evidence of metastatic disease. SUBJECTS AND METHODS: Thirty-three patients with 37 adrenal masses (19 metastases, 18 adenomas), all of whom had a known primary cancer, were studied with noncontrast CT and chemical-shift MR imaging (1.5 T). Lesion size and density in Hounsfield units (H) were determined by CT. Adrenal signal intensity normalized to that of spleen was used to calculate adrenal-spleen ratio (ASR), defined as the percentage of signal remaining in the opposed-phase image relative to the in-phase image. Lesions less than or equal to 0 H were classified as benign, lesions greater than 20 H were regarded as malignant, and lesions between 0 and 20 H were regarded as indeterminate. Diagnoses were confirmed by biopsy (for 19 lesions) or by follow-up imaging (for 18 lesions). An imaging algorithm was derived by determining the relative value of CT and MR imaging for diagnosing the lesions. The reimbursement rates for CT-guided biopsy and MR imaging of the abdomen were obtained from Medicare. RESULTS: All 13 lesions of 0 or less H were correctly classified as benign by CT. ASR was less than 70 in 10 of these 13. In another 13 lesions, H was greater than 20; all were malignant and all had an ASR greater than 80. Of 11 CT-indeterminate lesions, four of five adenomas had an ASR less than 70, and four of six metastases had an ASR greater than 80. Two malignant lesions had ASRs between 70 and 80 and were diagnosed by biopsy findings. One CT-indeterminate adenoma had an ASR of 84 and was diagnosed by biopsy findings. The reimbursement rate by Medicare is similar for CT-guided biopsy with pathologic interpretation and for MR imaging of the abdomen. CONCLUSION: An algorithm was developed for diagnosis of adrenal lesions that uses the density reading on noncontrast CT as the first step, with chemical-shift MR imaging for CT-indeterminate lesions. In this algorithm, lesions of 0 H or less may be regarded as benign and further work-up is not required. Lesions with a density greater than 20 H are likely malignant and should be biopsied when the result will influence management. For CT-indeterminate lesions, we recommend chemical-shift MR imaging. An ASR threshold of 70 indicates a benign lesion, and no further workup is required in these patients. Lesions with an ASR greater than 70 should have a biopsy performed, depending on the clinical situation. The above algorithm is cost-effective and reduces the number of biopsies required without reducing the sensitivity of detecting malignant lesions.