Oligometastatic ACC

ACC overview

Oligometastatic adrenocortical carcinoma (ACC) refers to a limited-burden metastatic state within stage IV ACC in which all known sites of disease may still be amenable to focal treatment. In practice, this concept is usually applied to patients with a small number of metastases, often lung- or liver-predominant, sometimes approximated by ENSAT stage IVa or by thresholds such as no more than five lesions and smaller lesion size.¹² It occupies an intermediate position between localized/resectable ACC and widely disseminated metastatic disease, and its clinical importance lies in whether selected patients can derive meaningful benefit from surgery, ablation, radiation-based local therapy, or staged multimodal treatment in addition to systemic therapy.³²

The available evidence suggests that some patients with limited metastatic burden experience longer disease control and survival when treated with aggressive local therapy, particularly when complete macroscopic treatment is feasible and disease biology appears indolent.⁴⁵⁶ However, this literature is dominated by retrospective institutional series, registry analyses, and selected case reports, with substantial confounding by indication and survivorship bias.⁷⁸⁹ As a result, oligometastatic ACC is better understood as a pragmatic treatment framework than as a prospectively validated biologic subtype.

Across studies, the strongest recurring signal is not that local therapy reliably cures metastatic ACC, but that carefully selected patients may achieve prolonged survival or delayed need for escalation of systemic treatment.³¹² Recurrence remains common even after apparently complete local treatment, and outcomes vary by metastatic pattern, disease-free interval, hormonal activity, and feasibility of complete resection or ablation.¹⁰⁵⁶ Clinically, this means oligometastatic management is usually considered in comparison with immediate systemic-only treatment for diffuse stage IV disease, not as a replacement for standard systemic therapy in biologically aggressive disease.

Diagnostic and staging context

Oligometastatic ACC is defined operationally rather than by a universally accepted staging rule. Reviews and retrospective series generally describe it as low-volume metastatic disease, often limited to one or two organ sites or a small number of lesions, with particular attention to lesions that are technically resectable or ablatable.³¹² This framing is clinically useful because treatment decisions depend less on stage IV status alone than on distribution of disease, lesion size, tempo of recurrence, and whether all visible disease can plausibly be controlled with local therapy.⁴²

What is reasonably reliable is that lower tumor burden and limited site involvement identify a more favorable subgroup within metastatic ACC. What is less reliable is any single numeric cutoff, because published definitions vary and are derived from retrospective datasets rather than prospective biologic validation.¹²

Major clinical patterns relevant to selection

Metachronous recurrence after primary adrenalectomy

A recurring favorable pattern is delayed metastatic recurrence after resection of the primary tumor, especially when the interval from adrenalectomy to metastasis is long. Longer disease-free interval has been associated with better outcomes after pulmonary metastasectomy and is commonly used as a surrogate for less aggressive tumor biology.¹⁰⁶ In this setting, local therapy is often pursued with the goal of extending disease control rather than expecting durable cure.

This association is one of the more consistent findings across surgical series, but it still arises from selected retrospective cohorts. The practical implication is that recurrence timing can help estimate whether aggressive local treatment is proportionate, especially when disease remains confined and technically treatable.¹⁰²

Synchronous low-volume metastatic disease

Some patients present with metastatic disease at diagnosis but still have limited-volume spread. Retrospective data suggest that complete macroscopic resection of the primary tumor, sometimes together with treatment of metastatic sites, may be associated with longer survival in selected patients than incomplete resection or no surgery.⁴⁷⁹ This has led to interest in cytoreduction or staged multimodal management rather than a uniform nonoperative approach for all stage IV presentations.

The reliable conclusion is only that selected synchronous metastatic patients may benefit from surgery when disease is limited and resection is feasible. It is not reliable to infer that upfront surgery is broadly beneficial across all metastatic ACC, because registry studies cannot fully account for performance status, occult disease burden, endocrine morbidity, or surgeon selection.⁸¹¹¹²

Site-specific metastatic patterns

Pulmonary-only metastases are the most consistently described setting for metastasectomy, with several series suggesting prolonged survival in selected patients after resection of lung lesions.¹⁰⁶ By contrast, benefit from surgery appears less consistent in liver-only disease in some population analyses, and outcomes are generally poorer with multiple metastatic sites.⁸¹³ These observations suggest that anatomic pattern may reflect both technical resectability and underlying disease biology.

This site-specific signal is clinically relevant but remains imperfect. Lung-limited disease appears to be the clearest scenario in which focal treatment is repeatedly associated with favorable outcomes, whereas liver-only or multisite disease warrants more caution and stronger emphasis on systemic therapy.⁸¹³²

Local and multimodal treatment strategies

Once oligometastatic disease is recognized, the next question is whether all visible disease can be treated with acceptable morbidity. Surgical metastasectomy remains the best-described local approach, particularly for lung lesions, and complete resection is generally favored when feasible.¹⁰⁶ Image-guided thermal ablation has also shown high technical success in small liver or lung metastases, with better local control for smaller lesions.⁵ Reviews further include SBRT and other locoregional modalities as options in selected patients, although supporting ACC-specific data are limited.²

These focal approaches are increasingly framed as components of multimodal care rather than standalone interventions. In low-volume metastatic ACC, combining mitotane-based systemic treatment with locoregional therapy has been associated with longer progression-free intervals, delayed need for chemotherapy, and occasional complete responses compared with systemic treatment alone.³¹ For synchronous disease, neoadjuvant systemic therapy has also been proposed as a way to identify tumors with nonprogressive biology before committing to major surgery.⁴¹¹¹²

What is reasonably reliable is that local therapy appears most useful when embedded in broader multidisciplinary management and directed at fully treatable disease. What remains uncertain is the optimal sequencing relative to EDP-mitotane, mitotane alone, or surveillance, because comparative data are retrospective and heterogeneous.³¹¹¹²

Outcomes and expectations

The overall pattern across reports is prolonged disease control in a minority of selected patients rather than frequent long-term eradication of metastatic ACC. Median survivals after pulmonary metastasectomy or image-guided ablation can be substantially longer than expected for unselected metastatic disease, but relapse after local treatment is common.¹⁰⁵⁶ Factors repeatedly associated with better outcomes include longer disease-free interval, lower metastatic burden, smaller lesions, complete local treatment, and limited site distribution.⁵¹²

These findings support a realistic treatment aim of prolonging survival and postponing progression rather than assuming cure. The practical implication is that patients should be counseled that aggressive local therapy may be worthwhile in selected circumstances, but continued surveillance and readiness for further systemic or local treatment remain essential.³²

Limitations and sources of bias

Interpretation of the oligometastatic ACC literature is limited by small sample sizes, institutional expertise effects, heterogeneous definitions, and retrospective selection of fitter patients with more favorable disease biology.⁷⁸⁹ Population-based studies showing benefit from primary tumor resection are particularly vulnerable to confounding, since patients offered surgery are often younger, less burdened by disease, and more likely to receive coordinated multimodal care.⁷¹³ Case reports illustrate feasibility of aggressive treatment in exceptional circumstances, including vascular extension, but they do not establish generalizable treatment effects.¹⁴

Accordingly, the most reliable use of this evidence is for patient selection and hypothesis generation, not for universal treatment rules. In practice, decisions should be individualized in a multidisciplinary setting, with explicit comparison against expected outcomes from systemic therapy alone and against the morbidity of repeated local interventions.¹¹²

Role in management and research

Within current ACC care, oligometastatic disease represents a subset in which treatment intent may shift from purely palliative systemic control toward combined systemic and local disease eradication where feasible.³² Primary adrenalectomy, metastasectomy, ablation, and other focal therapies are most often considered for patients with low-volume disease, favorable tempo, and a realistic chance of complete treatment of all known sites.⁴⁹ This approach is distinct from management of diffuse metastatic ACC, where systemic therapy remains the main therapeutic backbone.

Future work is needed to standardize the definition of oligometastatic ACC, identify biologic markers of indolent metastatic behavior, and clarify the sequencing of surgery and locoregional therapy with mitotane- or EDP-based systemic treatment.¹² Until prospective data emerge, the concept remains clinically useful but evidence-limited: a selected metastatic state in which aggressive multimodal management may improve outcomes for some patients, without eliminating the high overall risk of recurrence.

Included Articles

• PMID 21958765: This commentary highlights pulmonary metastasectomy as a potential option for carefully selected patients with ACC limited to lung metastases, noting prolonged overall survival in some patients despite short median disease-free survival and frequent relapse. Longer disease-free interval after adrenalectomy and lower primary tumor T stage were associated with better post-metastasectomy outcomes.¹⁰

• PMID 25092161: In selected patients with synchronously metastatic stage IV ACC undergoing surgery, complete macroscopic resection was associated with longer overall survival than incomplete resection, while neoadjuvant systemic therapy showed a nonsignificant trend toward better outcomes and may help identify surgical candidates.⁴

• PMID 29184417: A SEER-based retrospective analysis of 290 adults with stage IV ACC found that resection of the primary adrenal tumor was associated with longer overall and cancer-specific survival than no primary-site surgery, despite the observational design and missing prognostic details. The study highlights potential benefit of surgery in selected metastatic ACC patients while emphasizing the need for prospective validation.⁷

• PMID 31697884: A case of stage IV ACC with right atrial and inferior vena cava tumor thrombus plus small lung metastases achieved prolonged survival with multimodal treatment including extended adrenalectomy and thrombectomy, EDP-mitotane, later lung metastasectomy, and second-line chemotherapy. The report suggests selected patients with limited metastatic burden may benefit from aggressive combined local and systemic therapy.¹⁴

• PMID 32621242: In a retrospective series of 16 patients with oligometastatic ACC involving liver or lung metastases, image-guided thermal ablation achieved 97% complete ablation with median local tumor progression-free survival of 21 months and median overall survival of 48.6 months. Smaller lesion size favored local control, while progression-free survival after primary tumor resection and hormonal secretion predicted overall survival.⁵

• PMID 33481081: A population-based SEER analysis of adults with synchronous metastatic ACC found longer overall survival in selected patients who underwent primary adrenal surgery, with additional benefit from metastasectomy and chemotherapy. Survival association differed by metastatic pattern, with no apparent benefit from adrenal surgery in patients with liver-only metastases.⁸

• PMID 34143888: In adults with low-volume metastatic ACC defined as stage IVA disease with no more than two tumor sites, first-line mitotane combined with locoregional treatment was associated with longer time to chemotherapy, progression-free survival, and overall survival than mitotane alone, with complete responses observed only in the combined-treatment group.³

• PMID 35302610: In metastatic ACC, this letter argues that primary-tumor cytoreduction should remain a consideration when safe and feasible, while acknowledging retrospective selection bias. It highlights neoadjuvant chemotherapy as a possible tool to select surgical candidates and reduce the need for extensive resection, but emphasizes that prospective data are lacking.¹¹

• PMID 35302612: This letter argues that in metastatic ACC, cytoreductive resection of the primary tumor may be best positioned after 4 to 6 cycles of EDP-mitotane rather than upfront, so surgery is reserved for nonprogressing patients and can provide pathologic response and Ki-67 reassessment with prognostic value.¹²

• PMID 35681708: A retrospective single-center study of modified ENSAT stage IVa ACC treated with mitotane plus loco-regional therapies found disease control in 66.7% of patients, with longer time to second-line treatment and overall survival. Higher disease-control rates were associated with 5 or fewer metastases or maximum metastasis diameter under 3 cm, supporting a proposed definition of oligometastatic ACC.¹

• PMID 38398093: In ACC patients with metastases initially confined to the lungs, pulmonary metastasectomy was associated with median overall survival of 3.1 years, with 5- and 10-year survival of 35.5% and 32.8%. The number of lung nodules resected did not predict outcomes, while shorter disease-free interval to lung metastasis or early metastasectomy after adrenalectomy was linked to worse survival.⁶

• PMID 38463201: This retrospective National Cancer Database study of metastatic ACC found that primary tumor resection was associated with longer overall survival, and adding metastasectomy to primary resection was associated with further survival improvement, whereas metastasectomy alone was not associated with benefit after adjustment and propensity matching.⁹

• PMID 39162017: A SEER-based retrospective study of 543 patients with metastatic ACC found that primary adrenalectomy was associated with lower overall mortality after adjustment and landmark analysis, with the clearest signal in patients receiving systemic therapy and those with solitary lung-only metastasis, but not liver-only or multiple-site disease.¹³

• PMID 41292251: This review frames oligometastatic ACC as a selected metastatic subset, reasonably defined as stage IVa disease or up to five metastases smaller than 3 cm, in which multimodal management may improve disease control. Retrospective data support combining systemic therapy with surgery, SBRT, thermal ablation, or transarterial embolization in carefully chosen patients based on tumor burden, Ki-67, recurrence interval, and fitness.²

References

Footnotes

1. Loco-Regional Therapies in Oligometastatic Adrenocortical Carcinoma.. Cancers (Basel). 2022. PMID: 35681708. Local full text: 35681708.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

2. Oligometastatic adrenocortical carcinoma: definition and treatment.. Curr Opin Oncol. 2026. PMID: 41292251. Local full text: 41292251.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵

3. Combination of Mitotane and Locoregional Treatments in Low-volume Metastatic Adrenocortical Carcinoma.. J Clin Endocrinol Metab. 2021. PMID: 34143888. Local full text: 34143888.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸

4. Surgical resection of synchronously metastatic adrenocortical cancer.. Ann Surg Oncol. 2015. PMID: 25092161. Local full text: 25092161.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

5. Oligometastatic adrenocortical carcinoma: the role of image-guided thermal ablation.. Eur Radiol. 2020. PMID: 32621242. Local full text: 32621242.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

6. Pulmonary Metastasectomy for Adrenocortical Carcinoma-Not If, but When.. Cancers (Basel). 2024. PMID: 38398093. Local full text: 38398093.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

7. Primary site surgery for metastatic adrenocortical carcinoma improves survival outcomes: an analysis of a population-based database.. Onco Targets Ther. 2017. PMID: 29184417. Local full text: 29184417.md ↩ ↩² ↩³ ↩⁴ ↩⁵

8. Adrenal Surgery for Synchronously Metastatic Adrenocortical Carcinoma: A Population-Based Analysis.. World J Surg. 2021. PMID: 33481081. Local full text: 33481081.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

9. Surgical Management of Metastatic Adrenocortical Carcinoma.. World J Surg. 2024. PMID: 38463201. Local full text: 38463201.md ↩ ↩² ↩³ ↩⁴ ↩⁵

10. Invited commentary.. Ann Thorac Surg. 2011. PMID: 21958765. Local full text: 21958765.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷

11. Response to Letter to the Editor From Berruti et al: “Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival”.. J Clin Endocrinol Metab. 2022. PMID: 35302610. Local full text: 35302610.md ↩ ↩² ↩³ ↩⁴ ↩⁵

12. Letter to the Editor From Cosentini et al: “Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients’ Survival”.. J Clin Endocrinol Metab. 2022. PMID: 35302612. Local full text: 35302612.md ↩ ↩² ↩³ ↩⁴

13. The Effect of Adrenalectomy on Overall Survival in Metastatic Adrenocortical Carcinoma.. J Clin Endocrinol Metab. 2025. PMID: 39162017. Local full text: 39162017.md ↩ ↩² ↩³ ↩⁴

14. [Advanced Adrenocortical Carcinoma with Vena Caval Tumor Thrombus Treated with Extended Surgery and Subsequent Chemotherapy].. Hinyokika Kiyo. 2019. PMID: 31697884. Local full text: 31697884.md ↩ ↩²