Frequent antecedent nodules and diagnostic gaps in adrenocortical carcinoma

Figures

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  Figure 1. Cohort characteristics and benchmarking to published datasets. We compared demographic data from this cohort (WashU) to a combination of datasets published in the literature [37, 38, 42]. Reference datasets were chosen based on the following criteria: from expert tertiary care centers, included data points of interest, and provided sufficient documentation to support mutual exclusivity (including with the WashU cohort). The WashU cohort is biased in favor of older male patients (A, B), hormone excess (C), and high-grade disease (D). Patients typically presented in community hospital settings and were referred to academic medical centers for surgery (E). The WashU cohort had comparable R0 resection rates to reference datasets (F); patients with metastatic disease were excluded here, as 1 reference dataset reported resection status only for locoregional disease. Including all patients who received surgical resection of the primary tumor in the WashU cohort, R0 resection rates were higher at academic centers (G). In A, C, D, and F, the number of patients in each group is specified as “n = …” above each bar and includes all patients for whom relevant data were available. In B, violin…

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  Figure 2. Antecedent nodules were prevalent, indolent for years, and associated with a higher risk of death. (A) Among patients for whom adequate data at the time of diagnosis were available, 31.7% had documentation of an antecedent, ipsilateral adrenal nodule. (B and C) Patients with adrenocortical carcinoma (ACC) derived from antecedent adrenal nodules were diagnosed with ACC at older ages with smaller primary tumors. (D) Top, line plot depicts the growth of adrenal tumors over time, colored by individual patients; the final point reflects the maximum dimension documented on the surgical specimen or the last radiologic timepoint prior to nonsurgical intervention for ACC. Normalized time is calculated as years elapsed since the initial time point; median, 4.68 years. Bottom, swimmer plot depicts radiology read corresponding to each time point. (E) Final growth is calculated as the change in maximum dimension between the final radiologic time point and baseline, divided by total elapsed time in years. The horizontal line is drawn at 0.5 cm/year. Growth rate of ACC derived from antecedent nodules was greater than that of longitudinally observed contralateral benign adrenocortical tumors…

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  Figure 3. Nature of diagnostic workup prior to first intervention for adrenocortical carcinoma (ACC). (A) Most patients were not referred to endocrinology prior to the first intervention. (B and C) Endocrinology referral was associated with a more complete hormonal workup for pheochromocytoma and ACC. The proportion of patients with adequate workup is indicated above the bars. Adequate pheochromocytoma evaluation included the collection of metanephrines; adequate ACC evaluation included measurement of cortisol and dehydroepiandrosterone sulfate for all patients and aldosterone for patients with hypertension. (D) Types of biopsies prior to first intervention, with inset showing pathology reads of adrenal biopsies. (E) Reasons for adrenal biopsy were often inappropriate. Primary indicates primary team decision. Intra-op indicates being obtained during unsuccessful primary resection. (F) Adrenal biopsies were obtained irrespective of adequate pheochromocytoma workup. (G) Adrenal biopsy was associated with a higher risk of progression and death as a univariate and remained significant in multivariable models with stage and grade. Abbreviations: ACA, adrenocortical adenoma; ACT, adrenocortical…

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  Figure 4. Hormone secretion patterns and clinical correlates. (A) Hormone secretion patterns are broadly categorized into major groups in the outer ring. (B) Patients with any androgen production had larger primary tumors. (C) Patients with combined cortisol and androgen secretion tended to present with metastatic disease; those with predominant cortisol secretion tended to present with locally advanced disease. (D) Patients with predominant cortisol secretion had significantly less smoking exposure than patients with androgen secretion or hormonally silent tumors. Kruskal-Wallis with significant comparisons by Dunn's post-hoc test (according to Benjamini-Hochberg adjusted P) indicated by brackets; all other pairwise comparisons had adjusted P ≥ .05. (E) Using Cox regression analysis, any cortisol secretion as a univariate was associated with a high risk of progression and death. In models including all major hormonal secretion patterns, predominant androgen secretion was protective against progression.

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  Figure 5. Landscape of genomic alterations. Heatmaps depicting clinical genomics data. Adrenocortical carcinoma (ACC) samples are signified by columns, and genes targeted for alteration are signified by rows in the tumor (top, restricted to genes appearing in >1 patient and/or known to be recurrently altered in ACC [37, 58]) or germline (bottom). Tumor mutational burden (TMB, mutations/Mb) is depicted above the heatmaps. Samples are color-coded by antecedent nodule status, major hormone secretion pattern, sample site, programmed death-ligand 1 (PD-L1) percentage, and microsatellite instability status in the top rows according to the legend on the right. Tumor or germline alterations are also colored according to the legend on the right. In the top heatmap, the light gray box signifies that the gene was not reported to possess a pathogenic variant in the tumor. Some patients had more than 1 site submitted for sequencing; samples that come from the same patient are signified below the heatmap as follows: A1-A2 come from patient A, B1-B3 come from patient B, etc. Missing data are signified by white boxes. Abbreviation: VUS, variant of uncertain significance.

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  Figure 6. Clinical correlates of molecular profiling and survival benefits conferred by therapies. (A) Kaplan-Meier curves demonstrating that tumor cell cycle and/or Wnt pathway alterations are associated with shorter progression-free survival; log-rank P shown in the lower left corner. (B) Adrenocortical carcinoma (ACC) with high programmed death-ligand 1 (PD-L1; ≥1%) were more likely to be hormonally silent. (C) Additional therapeutic interventions were directed to patients with higher-grade disease. Localized therapies include procedural interventions targeting specific disease sites (eg, targeted radiation of the adrenal bed or surgical resection of recurrences). (D and E) Multivariable Cox regression analysis models the impact of systemic therapies (D) or localized therapies (E) on death. Across systemic therapies, mitotane exposure (which typically occurred in the adjuvant setting) was protective against death. Cytotoxic chemotherapy was associated with a higher risk of death, likely due to inadvertent therapy selection bias among patients with metastatic disease, as detailed in the text. Exposure to localized therapies was protective against death.