Current evidence across the treatment spectrum of adrenocortical carcinoma: a comprehensive scoping review

Abstract

Adrenocortical carcinoma is a rare and aggressive malignancy for which high-quality evidence to guide clinical decision-making remains limited. This scoping review aimed to map and synthesize the extent, nature, and direction of evidence across five therapeutic domains in the management of adrenocortical carcinoma. Following the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidance, MEDLINE, Embase, and the Cochrane Library were searched without date restrictions. Eligible sources included clinical trials, observational studies, systematic reviews, and clinical guidelines addressing any treatment modality for adrenocortical carcinoma. Data were extracted using a standardized form and synthesized narratively across domains. Evidence visualizations and an intervention-by-domain matrix were developed to identify areas of consistency, uncertainty, and research gaps. Forty-nine studies met the inclusion criteria. Complete tumor resection with negative margins consistently emerged as the strongest prognostic factor. Minimally invasive adrenalectomy showed comparable outcomes only in carefully selected low-risk patients. Adjuvant mitotane demonstrated potential benefit in high-risk disease but not in low- to intermediate-risk patients. In metastatic disease, multimodal management incorporating etoposide, doxorubicin, cisplatin, and mitotane, together with metastasectomy and local therapies, was associated with improved outcomes in selected cases. Recurrence was frequent and often occurred early, particularly in large or invasive tumors. Cortisol-secreting tumors were associated with higher postoperative morbidity and earlier recurrence. Although the available evidence is predominantly retrospective and heterogeneous, consistent patterns emerge that can inform clinical management. This review provides a structured evidence base for future consensus development and highlights priorities for further research.

Introduction

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the adrenal cortex, with an estimated annual incidence of 0.7–2 cases per million individuals. Prognosis remains poor, with 5-year overall survival typically ranging from 20 to 40%, largely depending on stage at diagnosis. Clinical management is commonly guided by the European Network for the Study of Adrenal Tumors (ENSAT) staging system and additional prognostic factors, including resection status, Ki67 proliferation index, hormonal secretion, and histopathological characteristics. The Weiss score is a nine-criterion histopathological system used to distinguish conventional adrenocortical carcinoma from benign adrenal cortical neoplasms. One point is assigned for each adverse microscopic feature, and a total score of three or more supports a diagnosis of malignancy. Together with ENSAT stage, resection status, Ki67 index, and hormonal phenotype, these pathological findings contribute to postoperative risk stratification and treatment planning.

Surgical resection continues to be the cornerstone of curative treatment; however, major uncertainties persist regarding optimal operative strategies, including the choice between open and laparoscopic approaches and the role of prophylactic versus therapeutic lymph node dissection. Beyond surgery, the use of adjuvant therapies also remains controversial. Mitotane is the reference agent in both adjuvant and advanced disease settings, yet its clinical benefit is variable and frequently offset by substantial toxicity, a narrow therapeutic window, the need for long-term therapeutic drug monitoring, and considerable interpatient variability in achieving therapeutic plasma concentrations. Radiotherapy and systemic chemotherapy are used selectively, although the supporting evidence is heterogeneous and often limited to small retrospective series.

Given the rarity of ACC and the resulting scarcity of high-quality comparative studies, treatment recommendations often rely heavily on expert consensus. In this context, the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo (ACE) commissioned this scoping review to systematically identify and map the available evidence on the medical and surgical management of ACC. The overarching review question was the following: what are the extent, range, and nature of the evidence regarding medical and surgical treatments for patients with ACC, and how has this evidence been reported in the literature? Specifically, we sought to describe the available evidence on surgical approaches, adjuvant therapies, management of recurrent and metastatic disease, and hormonal control in advanced hormone-secreting ACC.

A scoping review was considered the most appropriate methodological approach because the literature on ACC treatment is diverse, methodologically heterogeneous, and dispersed across multiple study designs, guidelines, and clinical reports. Unlike systematic reviews, which generally address narrowly focused questions and require a sufficiently coherent body of comparable evidence, scoping reviews are designed to map complex and heterogeneous fields, clarify concepts, and identify knowledge gaps. This review was therefore designed to provide a comprehensive and systematically assembled evidence base for a subsequent formal consensus process using the RAND/UCLA Appropriateness Method (RAM) (1), in which the available evidence would be integrated with expert clinical judgment.

Methods

This scoping review was conducted following the methodological guidance of the Joanna Briggs Institute (JBI) (2) and reported according to the PRISMA-ScR checklist (3). A detailed protocol describing the planned methods was published a priori in the Open Science Framework (OSF; https://osf.io/9gmwb).

The review question sought to map the breadth, extent, and nature of the evidence regarding medical and surgical treatments for ACC to support a subsequent RAND/UCLA Appropriateness Method consensus process. Eligibility criteria were defined using the Population–Concept–Context framework. We included studies involving patients diagnosed with ACC that addressed any medical or surgical treatment modality, including surgical approaches, adjuvant therapy, treatment of recurrent disease, management of metastatic disease, and hormonal control, and that were conducted in any healthcare setting or geographic region. Eligible sources included primary research studies of any design, clinical practice guidelines, consensus statements, and systematic reviews. Case reports, small case series (fewer than 10 patients), editorials, commentaries, and non-evidence-based opinion pieces were excluded to prioritize comparative observational studies, systematic reviews, and guideline-level sources, consistent with the objective of informing a RAND/UCLA Appropriateness Method consensus process. No date restrictions were applied, and studies in English or Spanish were included.

A comprehensive search of MEDLINE (via PubMed), Embase, and the Cochrane Library was undertaken, combining controlled vocabulary and free-text terms related to ACC and its therapeutic management. Search strategies were tailored for each database, refined iteratively, and documented in full in Supplementary Table 1 (see the section on Supplementary materials given at the end of the article). In accordance with the protocol, gray literature was not systematically searched; however, reference lists of all included studies were screened to ensure completeness and minimize the risk of missing relevant evidence.

All identified records were imported into EndNote for deduplication and subsequently screened in Rayyan (4). Two reviewers independently screened titles, abstracts, and full texts, resolving disagreements through discussion or, when necessary, consultation with a third reviewer. Reasons for exclusion at the full-text stage were documented. The study selection process is presented in a PRISMA-ScR flow diagram.

Data extraction was performed using a standardized form that was pilot-tested before full application. Extracted variables included study characteristics, population details, treatment domains, contextual information, key findings, and reported limitations. Extraction was conducted by one reviewer and verified by a second.

Consistent with scoping review methodology, critical appraisal was not used to determine study eligibility, exclude sources, weight findings, or generate pooled estimates. However, because this review was commissioned to inform a subsequent RAND/UCLA Appropriateness Method (RAM) consensus process, an additional descriptive assessment of methodological quality was performed to provide contextual information regarding the confidence and limitations of the available evidence (5). This assessment used AGREE II for guidelines (6), AMSTAR-2 for systematic reviews (7), RoB 2.0 for randomized trials (8), and ROBINS-I for nonrandomized studies (9). The results of this appraisal informed the subsequent consensus process but are not reported as part of the primary findings of the present scoping review. Because the review synthesized only publicly available data, ethics approval was not required.

Results

A total of 49 studies met the inclusion criteria and were incorporated into the scoping review after full-text screening (Supplementary Fig. 1, PRISMA flow diagram). These studies covered the major therapeutic domains relevant to the management of ACC: surgery, adjuvant therapy, treatment of metastatic disease, management of recurrence, and hormone excess. As recommended by PRISMA-ScR and JBI guidance, the evidence is presented narratively and visually to capture patterns across heterogeneous study designs, clinical contexts, and outcome measures.

To facilitate interpretation across domains, we developed three complementary visualizations summarizing the structure and direction of the available evidence. Figure 1 presents an evidence map integrating study design, volume of evidence, and direction of findings across domains. Figure 2 displays horizontal evidence strips that summarize, for each intervention, the number of studies and the direction of effect within each therapeutic domain. Figure 3 provides an intervention-by-domain evidence matrix that allows cross-comparison of where evidence is concentrated, sparse, or inconsistent.

Figure 1.

Evidence map of treatment strategies in adrenocortical carcinoma (ACC). This figure summarizes the distribution, quantity, and direction of available evidence across the five clinical domains examined in this scoping review: surgery, adjuvant therapy, metastatic disease, recurrence, and hormone excess. Each bubble represents a specific intervention or evidence focus within a clinical domain. Bubble size reflects the number of contributing studies, fill color indicates the overall direction of evidence, and shape identifies whether randomized evidence was available. The x-axis groups interventions according to clinical domain, whereas the y-axis displays the principal intervention or evidence category evaluated. The evidence map provides an integrated overview of the current ACC literature, highlighting areas supported by relatively consistent evidence (e.g. R0 resection, management in high-volume centers, EDP-M for advanced disease, metastasectomy in selected patients, and adjuvant mitotane in high-risk disease), areas where evidence remains limited or evolving (e.g. adjuvant platinum-based chemotherapy, locoregional therapies for metastatic disease, and repeat surgery for recurrence), and domains characterized by substantial uncertainty or sparse data (e.g. minimally invasive adrenalectomy in selected populations and hormone excess-specific management). ACC, adrenocortical carcinoma; RCT, randomized controlled trial; MIS, minimally invasive surgery; LND, lymph node dissection; EDP-M, etoposide–doxorubicin–cisplatin plus mitotane; TDM, therapeutic drug monitoring.

Figure 2.

Evidence summary across treatment domains in adrenocortical carcinoma (ACC). This heatmap summarizes the direction and quantity of evidence across the major therapeutic domains evaluated in this scoping review. Each tile represents a specific intervention or evidence focus within a clinical domain. Tile color reflects the overall direction of evidence, while the number displayed within each tile indicates the number of contributing studies. Green tones represent interventions associated with favorable outcomes, purple indicates neutral findings, orange denotes uncertain or conflicting evidence, red indicates unfavorable outcomes, and gray identifies descriptive domains where direction of effect was not applicable. The figure highlights areas supported by a larger body of evidence, such as minimally invasive versus open adrenalectomy, adjuvant radiotherapy, and adjuvant mitotane in high-risk disease, while also illustrating domains where evidence remains sparse, including hormone excess management and systemic therapies for recurrent disease. ACC, adrenocortical carcinoma; MIS, minimally invasive surgery; LND, lymph node dissection; EDP-M, etoposide–doxorubicin–cisplatin plus mitotane; TDM, therapeutic drug monitoring.

Figure 3.

Domain-by-intervention evidence matrix in adrenocortical carcinoma. Figure 3 displays an evidence matrix mapping each intervention to its corresponding therapeutic domain: surgery, adjuvant therapy, metastatic disease, recurrence, and hormone excess. Each bubble represents an intervention–domain pair. Bubble size indicates the number of studies informing that evidence cluster, bubble color denotes the overall direction of evidence, and bubble shape identifies whether randomized evidence was available. The x-axis lists the interventions or evidence categories identified in the review, while the y-axis groups them by clinical domain. This matrix complements the evidence map and heatmap by providing a cross-domain comparison of where evidence is concentrated, highlighting well-supported areas, such as R0 resection, high-risk adjuvant mitotane, EDP-M in advanced disease, and metastasectomy in selected patients; evolving areas, such as adjuvant platinum-based chemotherapy and locoregional therapy in oligometastatic disease; and domains with limited evidence, such as hormone excess-specific management.

Detailed characteristics of included studies for each domain are available in Supplementary Tables 2–6, corresponding to surgery (Supplementary Table 2), adjuvant therapy (Supplementary Table 3), metastatic disease (Supplementary Table 4), recurrence (Supplementary Table 5), and hormone excess (Supplementary Table 6). These tables summarize study design, populations, interventions, and key findings for all included literature.

The following sections synthesize the findings for each therapeutic domain, reflecting the breadth, methodological diversity, and recurring evidence gaps across the ACC literature.

Surgical management

Overview of the evidence base

The surgical domain encompassed observational evidence from large population-based databases, multi-institutional cohorts, single tertiary-center series, and several systematic reviews examining adrenalectomy for ACC. The evidence base was entirely nonrandomized and heterogeneous in design, sample size, and reporting quality but consistently underscored surgery as the central therapeutic modality across ENSAT stages I–IV. Collectively, these studies described the characteristics of surgical candidates, operative approaches, margins, surgeon expertise, and outcomes in both localized and advanced disease.

Surgical margins and prognosis

Achieving an R0 resection consistently emerged as the strongest surgical predictor of survival. In a high-volume tertiary-center experience (10), negative surgical margins were associated with markedly superior median OS compared with R1 or R2 resections, and margin status remained independently associated with prognosis after adjustment for stage and tumor biology. The study also provided granular detail on recurrence patterns, reporting higher rates of local relapse in margin-positive patients.

Passman et al. (11) reported similar findings in a contemporary multicenter cohort of patients with nonmetastatic ACC. Positive surgical margins were independently associated with significantly shorter OS and higher recurrence rates, even after adjustment for ENSAT stage and tumor biology. The study further highlighted that margin status exerted a stronger prognostic impact than tumor size or functional status, reinforcing its role as a critical determinant of long-term outcomes.

Multi-institutional evidence echoed this pattern. A large cohort across several international centers (12) demonstrated that R0 resection was strongly correlated with long-term survival, whereas R1 resections conferred substantially higher recurrence and mortality risks. This study also highlighted that patients requiring multivisceral resection or presenting with higher Weiss scores were more likely to experience margin positivity.

Additional tertiary-center series (13) reinforced the prognostic significance of margin status, and some small cohorts described differences in presentation and recurrence patterns in nonfunctioning tumors (14), noting that positive margins were associated not only with increased local recurrence but also with earlier recurrence intervals and the need for more frequent reoperations. These studies collectively support that R0 resection is not only desirable but essential for optimizing oncologic outcomes in ACC.

Surgical approach: open versus minimally invasive and robotic

Multiple studies compared open adrenalectomy with laparoscopic or robotic approaches, highlighting variations in surgical selection criteria across centers. Carnaille (15), in a pre-2011 systematic review, summarized perioperative and long-term data from contemporary series and identified consistent perioperative benefits with laparoscopy – reduced bleeding, postoperative pain, and hospital stay – but also raised concerns regarding capsular rupture and peritoneal carcinomatosis in some laparoscopic series. These concerns led to a recommendation in favor of open adrenalectomy when local invasion was suspected.

In the study by Passman et al. (11), the surgical approach also emerged as a relevant predictor of early oncologic outcomes. While laparoscopic adrenalectomy was employed in selected low-risk cases, the authors observed worse survival among patients with stage III disease undergoing a minimally invasive approach compared with open surgery. These results align with existing concerns regarding tumor violation and margin compromise in more advanced tumors, supporting the preferential use of open adrenalectomy when biological aggressiveness or radiologic invasion is suspected.

Subsequent observational cohorts (16, 17, 18) provided more nuanced data, showing that in carefully selected patients – typically ENSAT I–II tumors, <8–10 cm, without radiologic signs of invasion – laparoscopic adrenalectomy could achieve similar rates of R0 resection and comparable disease-free and overall survival to open surgery. However, these studies consistently reported significant selection bias, with the laparoscopic groups having smaller tumors, lower ENSAT stages, and lower Weiss scores. One study included in this group showed a higher adjusted recurrence risk with laparoscopy in larger lesions, suggesting that tumor size thresholds remain critical for approach selection.

A more recent systematic review and meta-analysis synthesized comparative evidence on open versus laparoscopic adrenalectomy for ACC, pooling data from 11 retrospective cohort studies including more than 1,600 patients. In this analysis, open surgery was associated with a significantly lower risk of positive surgical margins and more favorable 3-year overall and recurrence-free survival compared with laparoscopic adrenalectomy, while no consistent differences were observed at longer follow-up intervals. Laparoscopic surgery was associated with a shorter length of hospital stay, but perioperative complication rates were broadly comparable between approaches. Importantly, the authors emphasized that the observed oncologic differences were likely influenced by selection bias, tumor stage distribution, and center expertise, reinforcing the need for strict patient selection when minimally invasive approaches are considered for ACC (19).

Robotic adrenalectomy has been evaluated in two series (20, 21), both of which reported lower conversion rates and shorter hospital stays compared with conventional laparoscopy. While perioperative outcomes favored robotics, neither study demonstrated a survival advantage, and both emphasized the need for high surgical expertise, particularly given the steep learning curve associated with robotic adrenalectomy for ACC.

Analyses examining tumor size and surgical approach (22, 23) further highlighted that operative strategy should be guided by tumor characteristics. Larger tumors (>6–8 cm), radiologic evidence of invasion, and high functional activity were consistently associated with open resection. These studies also showed that minimally invasive surgery in larger tumors increased the risk of capsular rupture and compromised oncologic margins.

Finally, several series warned explicitly against laparoscopic adrenalectomy in the setting of known or suspected ACC (24, 25), citing higher rates of peritoneal carcinomatosis, earlier recurrences, and a higher frequency of intraoperative tumor violation. These reports strengthen the argument that minimally invasive approaches should be restricted to centers with extensive experience and applied only in strictly selected cases.

Surgical extent, lymph node dissection, and multivisceral resection

Evidence on surgical extent was reported by Vanbrugghe et al. (12), which detailed outcomes for patients requiring multivisceral resection due to organ invasion. This study showed that additional organ resection – most commonly involving the kidney, spleen, pancreas, or liver – was often necessary to achieve R0 status in ENSAT II–III disease. Patients undergoing multivisceral resection had significantly larger tumors and higher Weiss scores, and their operations were more complex. Despite these challenges, when R0 resection was achieved, survival outcomes could still be favorable, although interpretation remained limited by selection bias and differences in tumor biology.

Although not designed specifically to evaluate the therapeutic impact of lymphadenectomy, Passman et al. (11) reported that nodal evaluation was infrequently performed and did not demonstrate a clear association with overall survival. However, the authors noted that nodal metastases – when present – were strongly correlated with aggressive pathological features, consistent with prior evidence suggesting that lymph node involvement reflects advanced tumor biology rather than a modifiable surgical target.

Regarding lymphadenectomy, a recent SEER-based analysis (26) reported an association between the number of examined lymph nodes, nodal status, and cancer-specific mortality. Specifically, patients with pN1 disease had worse outcomes, and a higher lymph node count improved staging accuracy. However, the therapeutic benefit of lymphadenectomy remained unclear, as none of the included studies demonstrated a consistent survival advantage attributable to more extensive nodal dissection.

Surgeon and center expertise

The influence of surgical expertise was highlighted in a national cohort study (27), which compared outcomes between high-volume and low-volume surgeons. While overall survival was similar, recurrence rates and recurrence-free survival were substantially better in patients operated on at high-volume centers. The authors attributed these findings to more accurate preoperative staging, greater use of open surgery in appropriate cases, and higher consistency in achieving R0 resection.

Additional reviews (28) and institutional series (13) reinforced these findings, emphasizing that surgical outcomes in ACC improve significantly when procedures are performed by experienced surgeons with extensive expertise in both open and laparoscopic adrenalectomy. These data collectively support centralization of ACC care in high-volume tertiary centers.

Surgery in advanced and metastatic disease

Advanced disease was addressed in several reports (29), which showed that aggressive surgery in ENSAT III–IV disease can yield long-term survival in selected patients, although recurrence rates remained high. These studies typically included small samples but consistently reported that symptom relief, cytoreduction, and occasional long-term remission could be achieved in highly selected cases.

In metastatic disease (ENSAT IV), a population-based study (30) found an association between resection of the primary adrenal tumor and improved overall and cancer-specific survival. However, the effect was heavily confounded by indication – patients undergoing surgery were younger, had a lower metastatic burden, and were more likely to receive systemic therapy. Nevertheless, the study contributes evidence suggesting that resection of the primary tumor may have a role in selected metastatic patients as part of multimodal management.

Synthesis of key findings in surgical management

Overall, the surgical evidence consistently demonstrates that complete resection remains the cornerstone of ACC management, with R0 margins representing the strongest determinant of long-term outcomes. Open adrenalectomy is generally preferred when tumor size, imaging features, or local invasion raise concern for oncologic compromise, while minimally invasive approaches may be appropriate only in highly selected ENSAT I–II cases treated in expert centers. Lymph node dissection appears valuable primarily for staging rather than therapeutic benefit, and multivisceral resection may be required to achieve negative margins in locally advanced disease. Across studies, outcomes were superior when surgery was performed in high-volume centers by experienced teams, reinforcing the importance of centralization. In metastatic disease, resection of the primary tumor may offer benefit in carefully selected patients as part of a multimodal approach.

Adjuvant therapy

Overview of the evidence base

The adjuvant domain comprised eight studies, including retrospective institutional cohorts, a population-based registry analysis, one phase II clinical trial, and the first phase III randomized controlled trial in resected ACC. The evidence base remains fragmented due to small sample sizes and substantial heterogeneity in staging, margin status, dosing strategies, and treatment duration. Across all included studies, mitotane was the only systematically assessed adjuvant systemic therapy, occasionally combined with radiotherapy or cytotoxic chemotherapy in selected high-risk cases.

Adjuvant mitotane: effectiveness, therapeutic exposure, and tolerability

Most included studies evaluated mitotane as adjuvant therapy following complete macroscopic tumor resection. Observational evidence showed a variable but generally favorable association between adjuvant mitotane and recurrence-free survival (RFS), particularly among patients with high-risk pathological features.

Şişman et al. (31) reported outcomes from a small single-center cohort in which adjuvant mitotane, alone or combined with radiotherapy or chemotherapy, was associated with longer recurrence-free intervals compared with observation, although interpretation was limited by short and heterogeneous follow-up. Using a population-based dataset, Pedersen et al. (32), found that adjuvant mitotane was associated with longer RFS after adjustment for clinical and pathological covariates. Conversely, Ohmoto et al. (33) reported substantial interindividual variability in recurrence patterns among Japanese patients treated with mitotane in adjuvant and advanced settings.

Tang et al. (34) synthesized the available observational evidence in a systematic review and meta-analysis. Pooled analyses showed an association between adjuvant mitotane and improved RFS and overall survival compared with surgery alone. However, all included studies were retrospective and heterogeneous regarding disease stage, margin status, mitotane dosing, and treatment duration. The apparent benefit was largely driven by high-risk populations, and confounding by indication and selection bias limited causal interpretation.

In contrast, the ADIUVO randomized phase III trial (35), conducted in patients with completely resected low- to intermediate-risk ACC (R0 resection, ENSAT I–III, Ki67 ≤ 10%), found no statistically significant benefit of adjuvant mitotane over active surveillance for RFS or overall survival. Five-year RFS was 79% in the mitotane group and 75% in the surveillance group, reflecting the favorable prognosis of this population. However, recruitment was slow, event rates were low, and the trial did not reach its originally planned sample size, limiting statistical power. The prospective ADIUVO-Obs cohort similarly confirmed low recurrence rates in this risk category. These findings support surveillance as a reasonable strategy for low- to intermediate-risk patients while not excluding a potential role for mitotane in selected higher-risk populations.

Therapeutic exposure is important when interpreting mitotane effectiveness. Puglisi et al. (36) found that achieving plasma concentrations within the therapeutic range, generally 14–20 mg/L, was associated with longer RFS among patients receiving adjuvant treatment. A similar association between higher circulating concentrations and improved outcomes was observed in advanced ACC (37). Nevertheless, many patients did not reach or sustain target concentrations because of intolerance, dose-limiting toxicity, treatment interruptions, or early discontinuation.

Across studies, mitotane was consistently associated with gastrointestinal, neurological, and endocrine toxicity, which frequently limited adherence and the ability to maintain treatment for the recommended duration, often two years or longer (31, 32, 33, 36, 37). ADIUVO provided the strongest prospective tolerability data: all mitotane-treated patients experienced at least one adverse event, nearly one in five discontinued treatment because of toxicity or intolerability, and quality-of-life scores declined relative to surveillance (35). Thus, the potential effectiveness of adjuvant mitotane must be interpreted in relation to achieved plasma exposure, treatment duration, and the substantial tolerability challenges encountered in clinical practice.

Adjuvant platinum-based chemotherapy

Evidence for adjuvant cytotoxic chemotherapy in ACC remains limited. Early data derive from the phase II study by Abraham et al. (38), which primarily evaluated patients with advanced disease but included a small subset of postoperative patients treated with mitotane combined with doxorubicin, etoposide, and vincristine. Although some objective responses were reported, the study was not specifically designed to assess adjuvant therapy, and the available data were insufficient to support the routine use of postoperative chemotherapy in resected ACC.

In addition to mitotane, interest has emerged in adjuvant cytotoxic chemotherapy for patients at a particularly high risk of recurrence. Kimpel et al. (39) conducted a retrospective multicenter cohort study involving patients with radically resected ACC who exhibited adverse prognostic features, including high Ki67 indices, advanced ENSAT stage, venous tumor thrombus, or incomplete microscopic resection. Among 31 patients treated with adjuvant platinum-based chemotherapy and 31 matched controls, adjuvant treatment was associated with significantly prolonged recurrence-free survival and overall survival. Following adjustment for major prognostic factors and immortal time bias, the risk of recurrence was substantially reduced (adjusted HR: 0.19, 95% CI: 0.09–0.42), and overall survival was also improved (adjusted HR: 0.26, 95% CI: 0.09–0.72). Most patients received platinum-based regimens in combination with mitotane. Although the retrospective design and limited sample size preclude definitive conclusions, these findings provide the strongest available evidence supporting consideration of adjuvant platinum-based chemotherapy in selected patients with very high-risk ACC.

Despite these encouraging findings, the available evidence remains retrospective and susceptible to selection bias. Consequently, the role of adjuvant chemotherapy in ACC has not been definitively established. The ongoing ADIUVO-2 trial is a pragmatic, international, randomized phase III trial comparing adjuvant mitotane alone with mitotane plus four cycles of cisplatin and etoposide in patients with completely resected ACC at high risk of recurrence (ClinicalTrials.gov identifier: NCT03583710). The trial is expected to clarify whether adding platinum-based chemotherapy to mitotane improves recurrence-free survival in this population.

Adjuvant radiotherapy

Evidence evaluating radiotherapy as part of adjuvant management remains limited and is derived almost exclusively from retrospective cohorts. In the most methodologically robust study to date, Gharzai et al. (40) conducted a propensity score–matched analysis comparing patients who received adjuvant radiotherapy after curative-intent resection with matched controls treated with surgery alone. In this single-institution cohort (n = 78), adjuvant radiotherapy was associated with significant improvements in locoregional recurrence-free survival, overall recurrence-free survival, and overall survival, with a 3-year overall survival of 77.7% in the radiotherapy group compared with 48.6% in matched controls.

Foundational evidence supporting the role of adjuvant radiotherapy in locoregional control was provided by an early matched cohort analysis from the German Adrenocortical Carcinoma Registry. In this study, Fassnacht et al. (41) evaluated the impact of postoperative tumor bed radiotherapy after macroscopically complete resection and demonstrated a marked reduction in local recurrence among patients receiving adjuvant radiotherapy compared with matched controls treated with surgery alone. Five-year local recurrence-free survival was significantly higher in the radiotherapy group, whereas no differences were observed in disease-free or overall survival, reflecting the high incidence of distant metastatic progression in ACC. These early findings established the conceptual framework for radiotherapy as a modality primarily improving local control rather than long-term survival.

Earlier evidence from another high-volume tertiary center also supports a benefit of adjuvant radiotherapy in local disease control (42). In a matched cohort study of patients with localized ACC undergoing R0 or R1 resection, Sabolch et al. demonstrated a marked reduction in local recurrence with postoperative radiotherapy compared with surgery alone (local recurrence in 1/20 vs 12/20 patients, respectively). While adjuvant radiotherapy significantly improved local recurrence-free survival, no statistically significant differences were observed in recurrence-free or overall survival, likely reflecting limited sample size and competing risks from distant metastases.

Additional supporting evidence comes from an earlier retrospective cohort from the same institution, which evaluated both adjuvant and definitive radiotherapy in patients with primary and recurrent ACC (43). In this series, the use of radiotherapy was independently associated with a significantly lower risk of local failure, with patients treated without radiotherapy experiencing nearly a fivefold higher risk of locoregional recurrence. However, despite this consistent improvement in local control, radiotherapy was not associated with improved overall survival, underscoring that distant metastases remain the dominant driver of long-term outcomes in ACC.

Şişman et al. (31) similarly included a small number of patients treated with postoperative radiotherapy or chemoradiation in addition to mitotane. Although underpowered, this study suggested improved locoregional control among patients receiving radiotherapy, consistent with both historical institutional series and the more recent propensity-matched evidence supporting its use in margin-positive or other high-risk settings.

In contrast, not all retrospective series have demonstrated a benefit of adjuvant radiotherapy on survival outcomes. In a matched retrospective cohort from MD Anderson Cancer Center, Habra et al. (44) evaluated outcomes among patients who underwent primary surgical resection followed by adjuvant radiotherapy compared with matched controls treated with surgery alone. In this study, adjuvant radiotherapy was not associated with improvements in local recurrence-free survival, recurrence-free survival, or overall survival after adjustment for disease stage and adjuvant mitotane use. The authors highlighted the high rate of distant recurrence and suggested that the potential benefits of radiotherapy may be limited to selected high-risk patients rather than supporting its routine use in all resected ACC cases.

Supporting this risk-adapted interpretation, a large population-based analysis using the US National Cancer Database evaluated the impact of adjuvant radiotherapy in patients with nonmetastatic ACC undergoing surgical resection (45). In this cohort of 1,184 patients, adjuvant radiotherapy was not associated with an overall survival benefit in the unselected population. However, in prespecified subgroup analyses, adjuvant radiotherapy was associated with a significantly reduced risk of death among patients with positive surgical margins, with a 40% relative reduction in mortality after adjustment for concurrent chemotherapy and tumor-related factors. No survival benefit was observed in margin-negative patients or in other high-risk subgroups. Collectively, these findings suggest that any potential benefit of adjuvant radiotherapy is primarily confined to patients with incomplete (R1) resection.

Taken together, available retrospective and population-based evidence accumulated over nearly two decades consistently supports a role for adjuvant radiotherapy in improving locoregional control after resection of ACC, while its impact on overall survival remains inconsistent and appears limited to selected high-risk patients, particularly those with positive surgical margins.

Synthesis of key findings in adjuvant therapy

Overall, the adjuvant evidence indicates that mitotane is the only postoperative therapy with potential benefit, primarily among patients with high-risk ACC characterized by large tumors, higher ENSAT stage, positive margins, or Ki67 indices higher than 10%. In contrast, the ADIUVO randomized trial (35) demonstrated no advantage of mitotane in low- to intermediate-risk patients, supporting active surveillance as an appropriate strategy for this subgroup. Across studies, achieving and maintaining therapeutic plasma concentrations emerged as a critical determinant of benefit, although tolerability issues frequently limited sustained exposure. Evidence for adjuvant radiotherapy remains sparse but suggests potential value in selected high-risk cases. Evidence supporting adjuvant platinum-based chemotherapy remains limited and derives primarily from retrospective data; however, emerging evidence suggests a potential benefit in carefully selected patients with very high-risk disease. Prospective validation is still lacking.

Metastatic disease

Overview of the evidence base

The evidence base for metastatic adrenocortical carcinoma (mACC) included one international phase III randomized controlled trial, FIRM-ACT, together with predominantly observational evidence from single-center institutional cohorts, national population-based analyses, and multicenter surgical databases. FIRM-ACT provides the only randomized comparative evidence regarding first-line systemic therapy in advanced ACC. The remaining literature primarily evaluates multimodal strategies combining systemic therapy, locoregional interventions, and metastasis-directed surgery. Treatment approaches and patient-selection criteria were highly heterogeneous, and most observational studies were susceptible to selection bias and confounding by indication.

Systemic therapy and the role of mitotane and EDP-M

Randomized evidence in metastatic ACC remains extremely limited. The FIRM-ACT trial, the largest international phase III randomized controlled trial conducted in advanced adrenocortical carcinoma, compared etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) with streptozocin plus mitotane in 304 patients with unresectable locally advanced or metastatic disease (46). EDP-M achieved significantly higher objective response rates (23.2 vs 9.2%) and longer progression-free survival (5.0 vs 2.1 months; HR: 0.55, 95% CI: 0.43–0.69), although no statistically significant improvement in overall survival was observed (14.8 vs 12.0 months; HR: 0.79, 95% CI: 0.61–1.02). The absence of an overall survival benefit has been partly attributed to the crossover design, which allowed patients to receive the alternative regimen upon disease progression. Nevertheless, the trial established EDP-M as the reference first-line systemic regimen for advanced ACC and remains the highest-quality evidence available in this setting.

The Dutch population-based registry study by Debets et al. (47) reported outcomes for 167 patients treated between 2005 and 2020, showing that EDP-M (etoposide, doxorubicin, cisplatin plus mitotane) achieved a median overall survival (OS) of 11.8 months compared with 5.6 months in patients receiving other regimens, although this difference did not reach statistical significance after multivariable adjustment. Mitotane monotherapy was associated with the longest 5-year OS (11%), likely reflecting biological selection rather than drug efficacy. Importantly, both adrenalectomy of the primary tumor in the metastatic setting and local treatment of metastases (surgery, radiotherapy, or ablation) remained independently associated with improved survival.

In the largest and most detailed evaluation of this strategy, Boilève et al. conducted a retrospective cohort study assessing the combination of mitotane and locoregional treatments (LRT) in patients with low-tumor-burden metastatic ACC (mENSAT stage IVA, ≤2 metastatic organs) (48). Among 79 patients treated at a high-volume referral center, 73% received locoregional interventions – including surgery, interventional radiology, and radiotherapy – in addition to mitotane. Compared with mitotane alone, the combination strategy was associated with significantly longer progression-free survival, delayed time to first systemic chemotherapy, and markedly improved overall survival (median OS: 68 vs 22 months; adjusted HR: 0.18). Notably, all complete responses (13%) occurred in the combined treatment group, supporting a potential role for aggressive multimodal management in carefully selected oligometastatic patients.

Metastasectomy: synchronous versus metachronous

The US-ACCG multicenter cohort (49) provides the largest available dataset evaluating metastasectomy. Among 84 patients undergoing surgical resection of metastases, survival strongly favored metachronous metastasectomy – both from the time of primary adrenalectomy and from the time of metastasectomy – compared with synchronous procedures performed at the index operation. Longer disease-free interval (DFI > 12 months) was a consistent predictor of improved survival, while in the synchronous group, achieving an R0 resection was the key determinant.

Pulmonary metastasectomy

A 45-year single-center experience from the US National Cancer Institute (50) provides insight into pulmonary-only metastatic patterns. Among 75 patients, pulmonary metastasectomy achieved a median OS of 3.1 years, with 10-year survival exceeding 30% in selected cases. Notably, the number of nodules resected (median: 8, range: 1–75) did not influence survival, suggesting that lesion count alone should not preclude consideration of surgery. A DFI greater than 11 months from adrenalectomy to the development of lung metastases predicted better outcomes, while early recurrence (<11 months) was associated with poorer prognosis. These findings suggest that pulmonary metastasectomy may be appropriate in highly selected patients with indolent biological behavior and achievable complete resection.

Locoregional therapies for metastatic sites

Several studies have provided relevant evidence on nonsurgical locoregional approaches in metastatic ACC. In the Ohio State cohort (51), patients with liver metastases who received hepatic-directed therapy (TACE or SIRT) in addition to systemic treatment experienced significantly longer survival than those treated systemically alone. The Dutch registry (47) also found that local therapy for metastases – across lung, liver, and other sites – was independently associated with improved OS. Although both studies are subject to strong indication bias, together they suggest a role for locoregional approaches within a multimodal therapeutic plan for selected patients.

More recently, evidence has emerged supporting the use of image-guided thermal ablation in patients with oligometastatic ACC. In a retrospective single-center cohort, Veltri et al. (52) evaluated radiofrequency and microwave ablation of liver and lung metastases in patients with limited metastatic burden following resection of the primary tumor. High rates of complete ablation and durable local control were achieved, with prolonged local progression-free survival and encouraging long-term overall survival in carefully selected patients. These findings further support the concept that, in oligometastatic ACC, locoregional therapies may contribute to meaningful disease control within a multimodal management approach rather than serving solely a palliative role.

Collectively, these studies indicate that nonsurgical locoregional therapies – including embolization techniques and image-guided ablation – may have a role in carefully selected patients with limited metastatic burden, although prospective validation is required.

Clinical predictors and tumor biology

Across the metastatic studies, ENSAT stage at presentation, proliferative markers such as Ki67 (>20%), and the disease-free interval after initial adrenalectomy emerged as the most consistent prognostic factors. The presence of hormone-secreting tumors showed no prognostic value in the studies that assessed it. Notably, systemic therapies were rarely analyzed alongside mitotane levels or duration of exposure, limiting interpretation of the true contribution of drug effect versus biological variability.

Synthesis of key findings in metastatic disease

Across the available evidence, management of metastatic ACC relies on multimodal treatment strategies combining systemic therapy, metastasis-directed surgery, and locoregional approaches. EDP-M remains the standard systemic regimen, although population-based evidence suggests substantial variability in real-world effectiveness, with mitotane monotherapy performing favorably in selected biologically indolent cases. Metachronous metastasectomy offers the most consistent survival benefit, especially when performed after a prolonged disease-free interval, while synchronous metastasectomy appears justified only when an R0 resection is clearly achievable. Pulmonary-only metastases constitute a distinct scenario in which metastasectomy may yield long-term survival, independent of lesion count, provided disease biology is favorable. Locoregional hepatic therapies (TACE, SIRT) and local treatment of metastatic sites may improve outcomes in selected patients, although evidence is limited by indication bias. Overall, the certainty of evidence is low, dominated by retrospective cohorts and lacking randomized comparisons, yet consistent signals support individualized multimodal management in expert centers.

Recurrence

Overview of the evidence base

The recurrence domain was informed by three retrospective cohort studies: a large multicenter analysis from the US Adrenocortical Carcinoma Study Group (53), an institutional series from a high-volume tertiary center (54), and a recent single-center cohort study evaluating the management of postoperative recurrence in 106 patients with ACC (55), as well as a systematic review and pooled analysis of population-based studies (56). In the most comprehensive synthesis to date, Zhang et al. conducted a systematic review and meta-analysis including 11 retrospective population-based studies and 964 patients with recurrent ACC, evaluating the impact of reoperation compared with nonsurgical management. Together, these studies describe recurrence rates, timing, anatomical patterns, prognostic factors, and outcomes following recurrence after curative-intent adrenalectomy for ACC, while also evaluating the impact of adjuvant therapy, surgical expertise, and reoperation on survival. All included investigations were observational in nature and subject to selection bias, confounding by indication, and heterogeneous treatment strategies, particularly regarding surgical candidacy and systemic therapy use.

Patterns and timing of recurrence

Recurrence following curative-intent adrenalectomy was frequent in both cohorts, affecting roughly two-thirds of patients. The median time to recurrence was approximately 18–20 months, and most relapses occurred within the first two postoperative years. Distant recurrence predominated, with the lung and liver representing the most common sites, although around one-third of patients developed isolated locoregional disease. These consistent patterns across studies support an intensive surveillance strategy during the first 24 months after surgery, with emphasis on cross-sectional thoracic and hepatic imaging.

Predictors of recurrence

Several tumor-related features were consistently associated with higher recurrence risk. Larger primary tumors, higher T stage, and evidence of capsular or surrounding tissue invasion predicted shorter disease-free survival. In addition, anatomical lateralization showed a modest association with patterns of relapse.

Beyond tumor biology, the quality of the primary operation emerged as an important determinant of recurrence. Patients operated on at high-volume expert centers experienced lower recurrence rates, likely reflecting higher R0 resection rates, greater use of en bloc approaches, and less frequent utilization of minimally invasive techniques for high-risk tumors. These findings underscore that both tumor aggressiveness and surgical expertise contribute meaningfully to recurrence risk.

Management of recurrent disease

Management of recurrent disease has been evaluated primarily in retrospective cohorts, with limited prospective or randomized data. However, a recent systematic review and pooled analysis by Zhang et al. provides the most robust comparative evidence to date regarding the role of reoperation in recurrent ACC. Across 11 population-based retrospective studies, patients who underwent surgical resection for recurrence had significantly improved overall survival or survival after recurrence compared with those managed with nonsurgical therapies alone (pooled HR: 0.34, P < 0.001).

Importantly, the survival benefit was most pronounced in carefully selected patients. Factors associated with poorer outcomes after recurrence included multiple sites of recurrence, short disease-free interval (<12 months), advanced stage (ENSAT III–IV) at initial diagnosis, male sex, and non-R0 resection at the primary surgery. Among patients undergoing reoperation, complete resection of recurrent disease was the strongest predictor of prolonged survival, although even debulking or incomplete resection was associated with improved survival compared with nonsurgical management alone.

These findings support a role for repeat surgery in selected patients with recurrent ACC, particularly those with limited or oligometastatic recurrence, longer disease-free intervals, and a high likelihood of achieving complete resection. Nevertheless, the evidence remains subject to substantial selection bias, and the observed benefits likely reflect careful patient selection rather than a uniform effect of surgery across all recurrent cases.

Additional evidence supporting aggressive management of selected recurrent ACC was provided by Calabrese et al. (55), who retrospectively evaluated 106 patients with postoperative recurrence treated at a high-volume referral center. Recurrence presented as a single lesion in 35.8% of patients, multiple lesions within a single organ in 20.8%, and multi-organ disease in 43.4%. Locoregional therapies were used in all patients with isolated recurrence and in most patients with organ-confined multifocal disease, with surgery accounting for 86% of locoregional interventions. Following treatment of recurrence, 60.4% of patients achieved a disease-free state. Survival was significantly longer among patients with isolated recurrence compared with those presenting with multi-organ disease, supporting the use of surgery and other locoregional approaches in carefully selected patients with limited recurrent burden.

Adjuvant mitotane versus treatment at recurrence

Evidence regarding the role of mitotane outside the adjuvant setting derives predominantly from retrospective analyses evaluating its efficacy as monotherapy in advanced or recurrent ACC. Two contemporary cohorts provide the most robust data using modern imaging standards and RECIST-based response evaluation.

Megerle et al. (57) conducted the largest contemporary evaluation of mitotane monotherapy, including 127 patients with advanced or recurrent ACC treated across three German referral centers. Objective responses occurred in 20.5% of patients, including three complete responses, with an additional 25% achieving disease stabilization exceeding 180 days. Median progression-free survival and overall survival were 4.1 and 18.5 months, respectively. Two factors independently predicted improved outcomes: low tumor burden (<10 lesions) and initiation of mitotane at delayed recurrence (≥360 days after primary diagnosis). Patients meeting both criteria had a markedly higher likelihood of durable disease control (>6 months), whereas no objective responses were observed among those with early recurrence and high tumor burden. Achievement of mitotane plasma levels >14 mg/L correlated with better overall survival, although the relationship was confounded by treatment duration, and some responders never reached the therapeutic range. Collectively, these findings suggest that mitotane monotherapy may provide meaningful benefit predominantly in biologically indolent, low-volume recurrent disease.

In contrast, Reidy-Lagunes et al. (58) analyzed 36 patients with metastatic ACC treated with single-agent mitotane at a high-volume cancer center. Radiographic progression was the most common outcome (83%), and only 8% achieved complete response and 3% partial response. Importantly, all responders had nonfunctional tumors, excellent performance status, and low-volume, limited-site disease, with complete responses occurring in lesions <3 cm. Toxicity was substantial, with 44% experiencing grade ≥3 adverse events and 17% requiring long-term steroid replacement due to mitotane-induced adrenal insufficiency. These results reinforce that meaningful antitumor activity is restricted to a small, highly selected subgroup, and toxicity often limits sustained dosing.

Overall, evidence suggests that mitotane monotherapy displays limited efficacy in unselected recurrent or advanced ACC but can achieve durable responses in a minority of patients with low-burden, slowly progressive, nonfunctional tumors, particularly when recurrence emerges late after primary treatment. In contrast, patients with early relapse, high tumor burden, or rapidly progressive disease have minimal likelihood of benefit and are generally more appropriate candidates for cytotoxic chemotherapy-based regimens.

Synthesis of key findings in recurrence

Across the available evidence, recurrence after curative-intent surgery for ACC is common, tends to occur early, and is predominantly distant, involving the lungs and liver. Tumor size, local invasion, and advanced T stage are the most consistent predictors of relapse, while surgical expertise and achievement of complete resection significantly influence recurrence outcomes. Management of recurrent disease remains poorly defined in the literature, although consistent observational evidence suggests that carefully selected patients with isolated, organ-confined, or oligometastatic recurrence may derive substantial benefit from repeat surgery and other locoregional interventions. Contemporary cohort studies demonstrate that limited recurrence patterns are associated with improved survival and higher rates of secondary disease-free status, whereas outcomes remain substantially worse among patients with multifocal or multi-organ recurrence.

Hormone excess

Overview of the evidence base

The hormone-excess domain was informed by a single multicenter retrospective cohort evaluating outcomes after curative-intent adrenalectomy for cortisol-secreting versus nonsecreting ACC (59). This study provides the best available evidence regarding the clinical impact of endogenous hypercortisolism on postoperative morbidity, recurrence dynamics, and early oncologic outcomes. As a retrospective analysis spanning multiple centers over two decades, the evidence is subject to substantial confounding related to tumor stage, perioperative endocrine optimization, and variability in surgical management.

Patterns of hormonal excess and postoperative outcomes

Cortisol secretion was present in approximately one-fifth of resected ACCs. Patients with cortisol-secreting tumors experienced significantly higher postoperative morbidity compared with those with nonsecreting lesions. After adjustment for clinical and pathological covariates, secretion of cortisol remained independently associated with an increased risk of postoperative complications. These findings suggest that endogenous hypercortisolism contributes meaningfully to early postoperative vulnerability, likely mediated by well-known physiological effects such as immunosuppression, impaired wound healing, and metabolic instability.

Impact of cortisol secretion on recurrence

The presence of cortisol excess also had prognostic implications. Cortisol-secreting ACCs demonstrated significantly shorter recurrence-free survival, and cortisol hypersecretion remained an independent predictor of recurrence after multivariable adjustment. Median follow-up confirmed that relapse was common and occurred early, consistent with patterns observed across the broader recurrence literature. These results suggest that hormonal phenotype may influence tumor biology and should be considered in postoperative risk stratification.

Implications for perioperative management

The findings highlight the importance of endocrine optimization before and after adrenalectomy in patients with cortisol-secreting ACC. Perioperative management may require intensified glucocorticoid tapering strategies, correction of metabolic derangements, and careful monitoring for infectious and wound-related complications. As postoperative morbidity is substantially higher in this group, dedicated perioperative pathways may mitigate some of the complications associated with hypercortisolism.

Implications for postoperative surveillance

Given the association between cortisol secretion and earlier recurrence, intensified postoperative surveillance may be warranted. More frequent imaging and biochemical monitoring during the first two years after surgery may improve the timely detection of relapse. Incorporating cortisol secretion into prognostic models may enhance risk stratification and guide decisions related to adjuvant therapy, although direct evidence supporting adjuvant intensification based on hormonal phenotype remains limited.

Synthesis of key findings: hormone excess

Overall, patients with cortisol-secreting ACC experience not only higher postoperative morbidity but also a higher risk of early recurrence, highlighting the need for intensive endocrine management. Given these risks, more frequent postoperative surveillance and tailored endocrine optimization strategies could be implemented in these patients to mitigate the negative impacts of hypercortisolism on long-term outcomes. Although evidence is limited to a single retrospective cohort, the findings support the need for tailored perioperative endocrine management and more intensive postoperative surveillance in patients with cortisol-secreting ACC.

To facilitate interpretation of the evidence across domains, the principal findings and key limitations identified in this scoping review are summarized in Table 1. This summary highlights areas supported by relatively consistent evidence, domains where evidence remains limited or heterogeneous, and major gaps requiring future investigation.

Table 1.

Key evidence messages across therapeutic domains in adrenocortical carcinoma.

Domain	Key evidence message	Major limitations of evidence
Surgery	Complete (R0) resection remains the strongest predictor of favorable long-term outcomes. Open adrenalectomy is preferred for invasive or high-risk tumors, while minimally invasive approaches may be appropriate in selected ENSAT I–II cases treated in expert centers. Outcomes are consistently superior in high-volume centers.	Predominantly retrospective cohorts; selection bias regarding surgical approach and referral patterns.
Adjuvant therapy	Mitotane remains the principal postoperative systemic therapy, with the greatest potential benefit observed in patients at high risk of recurrence. Therapeutic drug monitoring appears important for treatment effectiveness. Adjuvant radiotherapy may improve locoregional control, while emerging retrospective evidence suggests a possible role for platinum-based chemotherapy in selected very high-risk patients.	One randomized trial (ADIUVO); most evidence remains retrospective, heterogeneous, and subject to confounding by indication.
Metastatic disease	EDP-M remains the reference first-line systemic regimen and is supported by the strongest available evidence. Metastasectomy and locoregional therapies may provide meaningful benefit in carefully selected patients as part of a multimodal strategy.	Limited randomized evidence; most studies involve highly selected patients treated in expert centers.
Recurrence	Recurrence is common and usually occurs within the first two postoperative years. Repeat surgery and other locoregional interventions may improve outcomes in patients with isolated, organ-confined, or oligometastatic recurrence.	Evidence is observational and highly susceptible to selection bias.
Hormone excess	Cortisol-secreting ACC is associated with worse clinical outcomes, increased postoperative morbidity, and higher recurrence risk, highlighting the importance of endocrine optimization and surveillance.	Evidence limited to a small number of retrospective studies.

Discussion

This scoping review examined key therapeutic domains in adrenocortical carcinoma (ACC): surgery, adjuvant therapy, metastatic disease, recurrence, and hormone excess, drawing from a diverse range of observational studies, systematic reviews, and two phase III trials. Overall, findings confirm the central importance of complete (R0) resection, the selective benefit of adjuvant mitotane in high-risk disease, and the potential role of metastasis-directed interventions in carefully chosen patients. Despite heterogeneity, the overarching patterns identified align closely with current expert guidance.

Our findings closely align with the 2018 ESE Clinical Practice Guidelines (60) and a recent practical clinical guide (61) particularly regarding key decisions in surgical approach, adjuvant mitotane therapy, and the management of metastatic ACC. This reinforces the relevance of the reviewed evidence in shaping current clinical standards. Our synthesis supports guideline recommendations favoring open adrenalectomy in large or invasive tumors, restricting minimally invasive surgery to highly selected low-risk cases, and emphasizing surgery in high-volume centers. Evidence for lymph node dissection and multivisceral resection remains limited and inconsistent, echoing guideline caution. In the adjuvant setting, our findings reinforce mitotane use in high-risk patients and, consistent with the ADIUVO trial (35) and the updated 2025 guidance, confirm no benefit for low-risk disease, supporting surveillance instead. Similarly, the observed dose–response relationship in therapeutic drug monitoring aligns with guideline emphasis on achieving target mitotane levels while highlighting practical challenges with tolerability.

For metastatic and recurrent ACC, the review corroborates the guideline-endorsed role of EDP-M as the systemic backbone and supports the selective use of metastasectomy and local therapies, particularly in patients with favorable disease-free intervals or limited metastatic burden. However, evidence remains almost entirely observational, and optimal sequencing of systemic and local treatments is poorly defined. Emerging conceptual frameworks further support this selective approach. Recent evidence has proposed an oligometastatic phenotype in adrenocortical carcinoma, suggesting that patients with limited metastatic burden, favorable disease biology, and prolonged disease-free intervals may benefit from metastasis-directed therapies. This framework should be regarded as hypothesis-generating and primarily reflective of retrospective selection patterns rather than a validated treatment paradigm, and requires prospective validation in future studies (62). In this context, aggressive metastasis-directed strategies – including metastasectomy, stereotactic radiotherapy, or other locoregional treatments – may achieve durable disease control and extended survival in carefully selected patients. This concept provides a biological rationale for the consistent survival advantages observed in patients undergoing metachronous metastasectomy, pulmonary metastasectomy, or local treatment of isolated metastatic sites across retrospective cohorts and helps reconcile the heterogeneity of outcomes reported in ENSAT stage IV disease.

Hormone excess – particularly hypercortisolism – was associated with worse perioperative outcomes and recurrence, consistent with guideline emphasis on aggressive endocrine optimization, yet research remains sparse in this area.

Despite areas of agreement with current guidelines, this review highlights several critical evidence gaps that limit the strength and applicability of existing recommendations. Prospective multicenter studies are urgently needed to refine the indications for adjuvant mitotane therapy, determine optimal dosing and duration, and establish best practices for therapeutic drug monitoring. In addition, future trials could explore novel therapeutic combinations or sequencing with systemic regimens to improve survival outcomes in high-risk ACC patients. Surgical uncertainties persist regarding the safe use of minimally invasive adrenalectomy in suspected ACC, the therapeutic value of systematic lymph node dissection, and criteria for multivisceral resection. Management of metastatic and recurrent disease lacks comparative prospective data to guide the integration and timing of systemic therapy, metastasectomy, and ablative procedures, particularly in relation to disease-free interval and tumor biology. Endocrine complications – especially hypercortisolism – remain understudied despite their prognostic relevance. Finally, the evidence base is dominated by specialized centers in high-income regions, with limited data from diverse healthcare systems, which constrains the generalizability of current recommendations. Addressing these gaps will be essential to optimize outcomes and refine future clinical guidelines and appropriateness statements.

Emerging therapeutic strategies for advanced ACC are currently under active investigation. Recent studies evaluating immune checkpoint inhibitors, including pembrolizumab (63), as well as chemo–immunotherapy combinations (64) have demonstrated encouraging responses and durable disease control in selected patients with heavily pretreated metastatic disease. However, the available evidence remains limited to small phase II studies and retrospective cohorts, with substantial heterogeneity in patient selection and treatment exposure. Consequently, although these approaches represent promising avenues for future research, they remain investigational and cannot yet be considered standard components of ACC management.

This review has limitations inherent to scoping methodology and the underlying literature. Most included studies were retrospective, small, and heterogeneous in staging, margins, treatment protocols, and outcome definitions, with substantial risk of selection bias and confounding by indication. We did not conduct meta-analyses, restricted inclusion to English and Spanish studies, and did not systematically search gray literature. Nonetheless, the structured domain-based synthesis and visual evidence maps provide a comprehensive and pragmatic overview of available evidence, supporting clinical decision-making and highlighting research priorities for a rare and complex malignancy. Accordingly, this review should be interpreted as a structured synthesis of the available evidence rather than a clinical practice guideline or consensus recommendation document. Its primary purpose is to provide the evidentiary foundation for future expert appraisal using the RAND/UCLA Appropriateness Method.

Conclusion

This scoping review provides a comprehensive domain-based synthesis of contemporary evidence on the management of ACC. Across 49 heterogeneous studies, several consistent signals emerged: complete (R0) resection remains the cornerstone of curative treatment; adjuvant mitotane offers potential benefit only in high-risk disease; and multimodal strategies integrating systemic therapy, metastasectomy, and local treatments may improve outcomes in selected patients with metastatic or recurrent ACC. Cortisol-secreting tumors carry higher postoperative morbidity and earlier recurrence, underscoring the importance of tailored endocrine management.

Despite general alignment with current international guidelines, evidence across all domains is limited – dominated by small, retrospective cohorts, variable reporting, and significant confounding. The resulting uncertainty highlights the need for prospective studies refining indications for adjuvant therapy, clarifying the role of minimally invasive and extended surgery, and defining optimal sequencing of systemic and metastasis-directed treatments. By mapping the breadth and nature of existing evidence, this review provides a structured foundation for the RAND/UCLA Appropriateness Method consensus process and supports the development of contextually relevant, evidence-informed recommendations for ACC care.

Commissioning body

This scoping review was commissioned and conducted under the auspices of the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo (ACE).

Declaration of interest

Diego F Ballen received speaker fees, advisory board honoraria, and research support from MSD, BMS, AstraZeneca, Amgen, Ipsen, Pfizer, and Merck. Alejandro Román-González received honoraria or institutional support from Amgen, PTC Therapeutics, Sanofi, Novo Nordisk, Ultragenyx, Novartis, Valentech, and Ipsen. Deyanira González-Devia received speaker honoraria from Glaxo, Curium Pharma, and NANETS. Luis F Fierro-Maya received speaker honoraria from Valentech and conference sponsorship from Recordati. Carlos E Builes-Montaño received consulting and speaking fees from Sanofi, Novo Nordisk, Novartis, Recordati Rare Diseases, Janssen, Chiesi, Abbott, and Boehringer Ingelheim and is a shareholder of Festina Lente. All other authors report no conflicts of interest.

Funding

This project was funded by the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo through an unrestricted educational grant from Valentech. Methodological support was provided by Festina Lente, contracted by the Asociación Colombiana de Endocrinología, Diabetes y Metabolismo. The sponsors had no role in the design, conduct, or reporting of this scoping review.

Author contribution statement

All authors conceived and designed the review. Carlos E. Builes-Montaño developed the search strategy and provided methodological oversight. All authors contributed to refinement of the review and approved the final version for submission.

Data availability

No primary data were collected for this scoping review. All data sources consist of publicly available literature.

Artificial intelligence disclosure

Artificial intelligence-assisted tools, including Grammarly and OpenAI, were used to support language editing, clarity, and manuscript drafting. These tools were not used for data generation, data analysis, result interpretation, or decision-making within the review process.