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. 2026 Mar 10;11(3):106092. doi: 10.1016/j.esmoop.2026.106092

Current clinical management and outcome of patients with adrenal cortical carcinoma (ACC) with rare histological subtypes—an ENSAT cohort study

O Kimpel 1,∗, D Cosentini 2, A Calabrese 3, A Jouinot 4,5, B Altieri 1,6, S Kircher 7, G Di Dalmazi 8,9, YS Elhassan 10,11, D Vassiliadi 12, K Chrysoula 12, S Puglisi 3, K Coscia 8,9, NV Gallego 13, P Loli 14, M Boudina 15, M Lagana 2, V Cremaschi 2, D Pignatelli 16, E Rios 17,18, CA Villavicencio 19, TJ McKenzie 19, N Rayes 20, CL Ronchi 10,11, I Bancos 19, M Terzolo 3, A Berruti 2, G Assié 4,5, M Kroiss 1,21, M Fassnacht 1,6,22
PMCID: PMC12995484  PMID: 41812315

Abstract

Background

In 2022, the World Health Organization (WHO) classified adrenal cortical carcinoma (ACC) into four subtypes: conventional, oncocytic, myxoid, and sarcomatoid. The differences in prognosis among these subtypes remain unclear. This European Network for the Study of Adrenal Tumours (ENSAT) multicentre study examines the differences not only in outcomes but also in the clinical management of patients with different ACC subtypes.

Patients and methods

Patient characteristics and survival data were retrospectively collected and analysed using Kaplan–Meier, multivariate Cox regression, and matched propensity score analyses (1 : 3 ratio) to compare recurrence-free survival (RFS) and overall survival (OS) for each subtype against conventional ACC. RFS was investigated only in patients after R0 resection, whereas OS was evaluated in the whole cohort. Matching was done for sex, age, and ENSAT tumour stage.

Results

The study included 1098 conventional, 179 oncocytic, 28 myxoid, and 10 sarcomatoid ACCs. RFS (in 653 conventional, 127 oncocytic, 15 myxoid, and 6 sarcomatoid ACCs) and OS (in all patients) were significantly longer in oncocytic ACC compared with the other groups, which was confirmed by multivariate Cox regression analyses {hazard ratio (HR) for RFS using conventional ACC as reference: oncocytic 0.47 [95% confidence interval (CI) 0.34-0.66], myxoid 0.92 (0.49-1.71), and sarcomatoid 0.83 (0.13-2.13) and for OS: oncocytic 0.37 (0.22-0.61), myxoid 1.02 (0.50-2.1), and sarcomatoid 0.82 (0.11-5.94)}. Similar results were seen after propensity score matching. RFS and OS were significantly longer in oncocytic ACC compared with the matched conventional ACC (RFS HR 0.41, 95% CI 0.29-0.55, P < 0.001; OS HR 0.35, 95% CI 0.24-0.52, P < 0.001).In metastatic oncocytic ACC, mitotane was similarly effective as in conventional tumours, but platinum-based chemotherapy seemed to result in longer progression-free survival.

Conclusion

Stage-adjusted outcome in oncocytic ACC is better than in other subtypes.

Key words: adrenal cancer, histological subtypes, prognosis

Highlights

  • •

    RFS and OS were significantly longer in oncocytic ACC compared with the matched conventional ACC.

  • •

    Treatment outcomes with mitotane and EDP plus mitotane, respectively, in oncocytic ACC were comparable to conventional ACC.

  • •

    Stage-adjusted outcome in oncocytic ACC is better than in other subtypes.

Introduction

Adrenal cortical carcinoma (ACC) is a rare endocrine malignancy with heterogeneous presentation and clinical course.1, 2, 3 In addition to different structural patterns in conventional ACC, consisting of diffuse, trabecular, nested, or alveolar patterns, three additional tumour subtypes (oncocytic, myxoid, and sarcomatoid) have been defined by the World Health Organization (WHO) classification of endocrine tumours.4 Key histological features and information on hormonal activity and diagnostic work-up are provided in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2026.106092.

Due to the difficulty in differentiating benign from malignant adrenal cortical tumours, various algorithms and scores, such as the Weiss, Hough, van Slooten, modified Weiss scoring systems, Lin–Weiss–Bisceglia (LWB) criteria, Helsinki score, and reticulin algorithm, have been used4, 5, 6, 7 to diagnose different ACC subtypes. The Weiss score is the most established and widely used score for differentiating malignant and benign cases among conventional ACC, but it has limitations in cases of oncocytic, myxoid, or sarcomatoid variants, and also in paediatric adrenal cortical neoplasm.5,8,9 In contrast, the Ki67 index seems to be a good prognostic factor in both conventional and non-conventional ACC subtypes.10

Survival in ACC depends largely on tumour stage, resection status, tumour grading, and hormone excess, all of which were recently combined to form the new prognostic S-GRAS score.2 In its early stages, and with limited risk factors, some patients can be surgically cured, but as the disease progresses to more advanced stages, the prognosis becomes increasingly unfavourable, with 5-year survival rates dropping to <20% for those with metastatic disease.1,2,11,12 However, some patients survive many years, and cases with complete treatment responses have been reported even in patients presenting with stage IV disease.13,14

The oncocytic variant represents ∼10% of adrenal cortical tumours and is the most prevalent among the subtypes followed by the myxoid and sarcomatoid variants, both of which are extremely rare.8,10 According to the 2022 WHO classification, oncocytic ACCs are composed of oncocytic tumour cells that account for >90% of the tumour.4 The histopathological diagnosis of malignancy in oncocytic neoplasms remains a challenge. A final diagnosis distinguishing between benign oncocytic tumour and oncocytic ACC could not be established histologically in up to 40% of cases.10,15 Currently, the most accepted scoring system is based on the LWB criteria.7

In addition, no specific gene expression patterns could discriminate oncocytic from conventional ACC in a study comprising six oncocytic ACCs,16 and the genetic alterations underlying this phenotype remain elusive. Recently, Kalomeris et al. published a comparative analysis between three conventional and two oncocytic ACCs reporting no significant differences in mutation load, microsatellite instability, or specific gene enrichment.17 In addition, a study using germline next-generation sequencing found similar potentially pathogenic variants in conventional ACC and in few oncocytic and myxoid subtypes.18

The myxoid and sarcomatoid variants are in turn much rarer than the oncocytic subtype.8 The first myxoid ACC was reported in 1979 by Tang et al.19 The myxoid subtype is characterised by tumour cells arranged in cords, clusters, or pseudoglandular structures with a prominent myxoid stromal background. These myxoid areas can involve focal or the entire tumour tissue. Myxoid and conventional ACCs seem to resemble regarding the clinical, immunohistochemical, and ultrastructural findings.20, 21, 22 Another unusual feature described in a single case of myxoid ACC is the presence of lipomatous metaplasia, which was previously thought to be associated only with benign adrenal cortical lesions.23

Sarcomatoid carcinomas contain carcinomatous and sarcomatous differentiation. They have been identified in different organ and tissue sites, including kidney, bladder, lung, breast, and oesophagus.24, 25, 26 ACCs with sarcomatous areas represent an extremely rare type of malignancy of unknown molecular pathogenesis.27 The first case was reported by Collina et al. in 1989.28

Together with numerous case studies,7,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 the currently published number of cases found through our PubMed search until April 2025 amounts to a total of only 184 patients with oncocytic ACC,10,43, 44, 45, 46, 47, 48, 49 22 with sarcomatoid,27,50, 51, 52, 53 and 57 with myxoid20,45,50,54 subtypes. To-date survival analysis showed conflicting results in oncocytic ACC.43,48 Renaudin et al. demonstrated longer survival in 43 patients with oncocytic adrenal tumours (28 oncocytic ACC) compared with 37 conventional ACCs.10 In addition, oncocytic ACC appeared to show improved overall survival (OS) in comparison to conventional ACC.10,44,48 In contrast, a recently published study could not find any differences in disease-free survival and OS between 21 oncocytic and 214 conventional ACCs.43 However, all these studies together included only 66 patients with oncocytic ACC. Data investigating survival in myxoid and sarcomatoid ACC compared with conventional ACC are lacking. Thus, it is not known whether the subtype influences survival and there are still no recommendations on whether histological subtype should guide treatment decisions.

Therefore, we designed a retrospective multicentre cohort study aimed to investigate the outcomes of different ACC subtypes in comparison to conventional ACC.

Patients and methods

Study population

This is a retrospective, international, multicentre study conducted on behalf of the European Network for the Study of Adrenal Tumours (ENSAT) (www.ensat.org).

The recruitment was carried out in 13 European reference centres for ACC (Würzburg, Germany; Munich, Germany; Leipzig, Germany; Brescia, Italy; Orbassano, Italy; Milan, Italy; Bologna, Italy; Paris, France; Porto, Portugal; Athens, Greece; Thessaloniki, Greece; Gijón, Spain; Birmingham, UK) and one centre in Rochester, USA. The study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the local ethics committees or institutional review boards at all participating institutions (Würzburg #88/11 on 17 May 2011). All patients who participated in this study provided written informed consent.

Patients aged >18 years with proven ACC and a histological report indicating the ACC subtype were included. Conventional ACCs from the centre in Würzburg were analysed as a control cohort. The study included cases treated between 2000 and 2022, with data follow-up extending until October 2024.

Data collection included various demographic, clinical, and histological parameters sourced from both the ENSAT ACC registry and patients’ medical records and included into a RedCap database. These parameters included factors such as sex, age at diagnosis and treatment, evidence of hormonal overproduction, resection status, and ENSAT tumour stage.12 The S-GRAS score was calculated using tumour stage, Ki67 index, resection status, age, and symptoms at diagnosis, including both hormonal activity and mass effect.2 Tumour staging at the time of diagnosis relied on imaging studies and findings from surgical procedures and pathological examinations. Details on treatment including duration, medication used, and response were also included if available.

The accuracy of histological diagnoses was assured through confirmation by experienced adrenal pathologists in each centre. In only 15 patients, the diagnosis was based on the judgement of the local adrenal expert pathologist. We included histological parameters such as the subtype, Ki-67 index, Weiss score, LWB score, and Helsinki score. Oncocytic ACCs were included if the histological report confirmed a minimum of ≥90% oncocytic tumour cells.4 Patients were excluded if relevant histological information or follow-up data were lacking.

Outcome assessment

Recurrence-free survival (RFS) and OS represented the main outcomes. RFS was investigated for all patients with R0 resection (R0 means microscopically complete tumour resection, indicating that no residual tumour is present at the resection margins on histopathological examination). It was defined as the time (in months) from primary diagnosis to the first radiographic or pathological evidence of recurrence. OS was defined as the time (in months) from the date of diagnosis to date of death due to ACC or last known follow-up. OS was evaluated in the whole cohort.

We based the assessment of objective response (OR) to medical treatment on local routine radiological evaluations, in analogy to RECIST 1.1. The primary endpoint was investigating the differences in RFS. Secondary endpoints were OS, OR rate to mitotane (in an adjuvant setting or advanced disease), and response to platinum-based chemotherapy in combination with mitotane.

In explorative analyses, we investigated differences among the histological subtypes with regard to clinical presentation (age, sex, tumour size, hormonal excess, Ki67 index, mitotane, and chemotherapy treatment).

Statistical analysis

Patients who did not experience progression or death were considered as censored at last follow-up. Due to the limited sample size of patients with myxoid and sarcomatoid ACC, these analyses should be considered as exploratory.

Statistical analysis included the use of Fisher’s exact test or the Wilcoxon rank-sum test where appropriate. RFS and OS were evaluated by Kaplan–Meier survival curves and differences between groups were evaluated using log-rank statistics. In addition, we carried out univariate and multivariate Cox regression analyses. Factors associated with RFS and OS were identified by univariate analysis and further evaluated by multivariate analysis if P < 0.10. For these analyses, the following factors were evaluated: histological variant, median age at primary diagnosis, sex, glucocorticoid excess, median Ki67 index, median tumour size, ENSAT stage at primary diagnosis, and resection status at primary diagnosis. In addition, a 1 : 3 matched propensity score analysis was carried out between each subtype and conventional ACCs after matching for age, sex, and ENSAT tumour stage.

All reported P values are two-sided, and statistical significance was considered when P < 0.05. Data analysis was conducted using SPSS version 29 (IBM SPSS Statistics, Armonk, NY).

Results

Patient characteristics

A total of 1315 patients diagnosed with conventional (n = 1098), oncocytic (n = 179), myxoid (n = 28), or sarcomatoid ACC (n = 10) met our initial inclusion criteria. Patient characteristics, pathological features, and treatment of these patients are presented in Table 1. There were no differences in age, sex, and tumour size between the four groups. However, there were significant differences regarding glucocorticoid excess, ENSAT stage, resection status, Ki67 index, and medical treatment between the groups (see Table 1).

Table 1.

Baseline characteristics and primary endpoints of the whole cohort

Oncocytic
 Myxoid
 Sarcomatoid
 Conventional
 P
ACC
 ACC
 ACC
 ACC
n = 179 n = 28 n = 10 n = 1098
Median age at primary diagnosis, years (IQR) 50 (41-60) 51 (41-64) 57 (49-72) 51 (40-62) 0.45
Sex, n (%)
 Male 71 (39.7) 15 (54.6) 6 (60.0) 415 (37.8) 0.071
 Female 108 (60.3) 13 (46.4) 4 (40.0) 683 (62.2)
Glucocorticoid excess, n (%)
 Yes 51 (28.5) 15 (53.6) 0 240 (21.9) 0.001
 No 74 (41.3) 6 (21.4) 5 (50) 485 (44.2)
 Unknown 54 (30.2) 7 (25) 5 (50) 373 (33.9)
ENSAT stage at primary diagnosis, n (%)
 1 15 (8.5) 3 (10.7) 0 (0.0) 73 (6.6) 0.001
 2 122 (68.1) 11 (39.3) 3 (30.0) 510 (46.4)
 3 33 (18.4) 10 (35.7) 4 (40.0) 265 (24.2)
 4 9 (5.0) 4 (14.3) 3 (30.0) 250 (22.8)
Resection status at primary diagnosis, n (%)
 0 127 (70.9) 15 (53.6) 6 (60.0) 653 (59.5) 0.001
 1 21 (11.7) 4 (14.3) 2 (20.0) 106 (9.7)
 2 4 (2.2) 1 (3.6) 0 151 (13.8)
 X 27 (15.1) 8 (28.6) 2 (20.0) 188 (17.1)
Initial surgical technique, n (%)
 Open 103 (57.6) 20 (71.4) 8 (80.0) 908 (82.7) 0.072
 Minimally invasive (MIS) 32 (17.9) 1 (3.6) 1 (10.0) 131 (11.9)
 MIS conversion to open 16 (8.9) 6 (21.4) 0 55 (5.0)
 Missing data 28 (15.6) 1 (3.6) 1 (10.0) 4 (0.4)
Median tumour size, mm (IQR) 100 (65-150) 107 (73-135) 150 (97.5-190) 105 (77.75-150) 0.73
Histology
 Median Ki67 index of the primary tumour, % (IQR) 11 (5-20) 24 (17-40) 20 (5-40) 15 (10-30) 0.001
 Median Weiss score, n (IQR) 5 (3-7) 5 (4-6) 5 (3-6) 5 (3-7) 0.56
 Median Lin–Weiss–Bisceglia minor criteria, n (IQR) 2 (1-3) NA NA NA
 Median Lin–Weiss–Bisceglia major criteria, n (IQR) 1 (1-2) NA NA NA
 Median Helsinki score, n (IQR) 20 (10-38) 38 (30.5-73) NA ND
Median S-GRAS score, n (IQR) 2 (2-3) 3 (3-5) 3 (1-6) 3 (2-4) 0.012
Medical treatment
 Mitotane yes, n (%)a 112 (62.6) 25 (89.3) 7 (70.0) 859 (78.2) 0.025
 In adjuvant setting, n (%) 82 (45.8) 19 (67.8) 4 (40) 379 (34.5)
 In advanced disease, n (%) 45 (25.1) 10 (35.7) 6 (60) 659 (60.0)
 Chemotherapy yes, n (%) 40 (22.3) 12 (42.9) 6 (60.0) 508 (46.3) 0.001
 In adjuvant setting, n (%) 2 (1.1) 2 (7.1) 1 (10) 29 (2.6)
 In advanced disease, n (%) 38 (21.2) 10 (35.7) 5 (50) 493 (44.9)
Outcome data
 Recurrence, n (%) 48 (37.0) 12 (80.0) 5 (83.0) 447 (68.0) 0.001
 Median months until recurrence (IQR) 104.5 (58.2-150.8) 21.7 (13.8-29.6) 14.3 (1.3-43.7) 21.4 (18.5-24.3) 0.001
 Median overall survival, months (IQR) 261.6 (102.5-420.7) 53.4 (26.1-80.5) 92.2 (8.3-107.5) 58.9 (50.4-67.5) 0.001
 Dead yes, n (%) 30 (16.8) 14 (50) 5 (50) 608 (55.4) 0.001
 Median time of follow-up, months (IQR)b 51.8 (22.9-89.5) 38.2 (12.9-66.5) 82.1 (3.8-126.7) 54.1 (24.1-116.9) 0.39
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ACC, adrenal cortical carcinoma; IQR, interquartile range; NA, not available; ND, not done.

a

Several patients have received mitotane both in an adjuvant setting and later in advanced disease.

b

In patients still alive.

After this part an additional sentence should be included: The patient selection is shown as a consort diagram in Supplementary Figure S1.

RFS in patients after complete resection

Survival analysis was carried out for patients with a complete surgical resection (R0) using RFS.

A total of 653 patients with conventional ACC, 127 patients with oncocytic ACC, 15 patients with myxoid ACC, and 6 patients with sarcomatoid ACC had a complete resection (R0). A total of 447 patients with conventional ACC (68%), 12 patients with myxoid ACC (80%), and 5 patients with sarcomatoid ACC (83%) developed a recurrence compared with only 48 patients with oncocytic ACC (37%, P < 0.001) after a complete surgical resection. Accordingly, patients with oncocytic ACC had a significantly longer median RFS with 104.5 months compared with conventional ACC (21.4 months), myxoid ACC (21.7 months), and sarcomatoid ACC (14.3 months) (P < 0.001, Figure 1). Median OS was also significantly longer in oncocytic ACC with 261 months compared with 58 months (conventional), 53 months (myxoid), and 92 months (sarcomatoid) (P < 0.001). Multivariate analysis identified median age <51 years, ENSAT stage 1 and 2, Ki67 index <15%, and the oncocytic variant to be associated with longer RFS.

Figure 1.

Figure 1

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Kaplan–Meier survival curves for recurrence-free survival (RFS) and overall survival (OS).

Mortality of the total cohort

OS was carried out in the whole cohort. Only 30 patients with oncocytic ACC (16%) had died at last follow-up compared with 608 (55%) patients with conventional ACC, 14 (50%) patients with myxoid ACC, and 5 (50%) patients with sarcomatoid ACC (P < 0.001). Table 2 and Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2026.106092, present the results of the uni- and multivariate analyses for RFS and OS of the whole cohort. Multivariate analysis identified median age <51 years, ENSAT stage 1 and 2, Ki67 index <15%, and the oncocytic variant to be associated with longer OS.

Table 2.

Prognostic factors for recurrence-free survival (RFS)

n Median RFS (months) Univariate analysis
 Multivariate analysis
HR 95% CI P HR 95% CI P
Histological variant
 1 conventional 653 21.4
 2 oncocytic 127 104.5 0.44 0.29-0.79 <0.001 0.47 0.34-0.66 <0.001
 3 myxoid 15 21.7 0.92 0.47-1.69 0.86 0.92 0.49-1.71 0.68
 4 sarcomatoid 6 14.3 0.95 0.36-2.34 0.49 0.83 0.13-2.13 0.88
Median age at diagnosis
 ≤51 years 454 20.1
 >51 years 347 14.9 1.28 1.23-1.46 <0.001 1.35 1.16-1.59 <0.001
Sex
 Male 291 16.7
 Female 510 16.7 1.06 0.93-1.20 0.41
Glucocorticoid excess
 No 362 15.9
 Yes 439 17.2 0.93 0.82-1.07 0.31
Median tumour sizea
 ≤105 mm 401 21.2
 >105 mm 400 14.4 1.37 1.21-1.56 <0.001 1.11 0.95-1.31 0.19
Median Ki67a
 ≤15% 422 30
 >15% 379 9.4 2.54 2.17-2.96 <0.001 1.88 1.59-2.23 <0.001
ENSAT stage
 1 + 2 435 28.1
 3 239 12.7 2.48 1.81-3.40 <0.001 1.61 1.31-1.96 <0.001
 4 127 8 4.62 3.36-6.35 <0.001 2.92 2.27-3.77 <0.001
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Only factors that showed at least a trend in the univariate analysis with P < 0.1 were further investigated by multivariate analysis.

ACC, adrenal cortical carcinoma; CI, confidence interval; ENSAT, European Network for the Study of Adrenal Tumours; HR, hazard ratio.

a

Of the primary tumour.

RFS and mortality of matched oncocytic, myxoid, and sarcomatoid ACC with conventional ACC

Due to the fact that ENSAT stage was unevenly distributed between the different subtypes, we carried out an additional evaluation of the influence of the histology on outcome using a 1 : 3 propensity score-matched analysis including sex, age, and ENSAT stage for each subtype. All patient characteristics, pathological features, treatment of patients for each subtype, and the matched conventional ACC are presented in Table 3.

Table 3.

Patient characteristics and primary endpoints of oncocytic, myxoid, and sarcomatoid ACC matched 1 : 3 with conventional ACC

Oncocytic
 Conventional
 P Myxoid
 Conventional
 P Sarcomatoid
 Conventional
 P
ACC
 ACC
 ACC
 ACC
 ACC
 ACC
n = 179 n = 537 n = 28 n = 84 n = 10 n = 30
Median age at primary diagnosis, years (IQR) 50 (41-60) 50 (41-59) 0.64 51 (41-64) 54 (36-65) 0.66 57 (49-72) 55 (51-69) 0.85
Sex, n (%)
 Male 71 (39.7) 234 (43.6) 0.38 15 (53.6) 28 (33.3) 0.057 4 (40) 4 (13.3) 0.09
 Female 108 (60.3) 303 (56.4) 13 (46.4) 56 (66.7) 6 (60) 26 (86.7)
Hormonal excess, n (%) 82 (45.8) 286 (53.3) 0.62 21 (75) 46 (54.8) 0.001 0 13 (43.3) 0.04
ENSAT stage,an (%)
 1 + 2 137 (76.5) 410 (76.4) 0.94 14 (50) 36 (42.9) 0.79 3 (30) 9 (30) 1.0
 3 33 (18.4) 103 (19.2) 10 (35.7) 33 (39.3) 4 (40) 12 (40)
 4 9 (5.0) 24 (4.5) 4 (14.3) 15 (17.9) 3 (30) 9 (30)
Resection status,an (%)
 0 127 (70.9) 383 (71.3) 0.24 15 (53.6) 43 (51.2) 0.47 6 (60) 13 (43.3) 0.41
 1 21 (11.7) 42 (7.8) 4 (14.3) 9 (10.7) 2 (20) 5 (16.7)
 2 4 (2.2) 24 (4.5) 1 (3.6) 12 (14.3) 7 (23.3)
 X 27 (15.1) 88 (16.4) 8 (28.6) 20 (23.8) 2 (20) 5 (16.7)
Initial surgical technique, n (%)
 Open 103 (57.5) 420 (78.2) 0.09 20 (71.4) 71 (16.7) 0.001 8 (80) 28 (93.3) 0.001
 Minimally invasive (MIS) 32 (17.9) 69 (12.8) 1 (3.6) 9 (10.7) 1 (10) 1 (3.3)
 MIS conversion to open 16 (8.9) 45 (8.4) 6 (21.4) 3 (3.6) 1 (3.3)
 Median tumour size,a mm (IQR) 100 (65-150) 105 (77-145) 0.78 107 (73-135) 110 (81-140) 0.99 150 (97-190) 109 (75-141) 0.79
 Median Ki67 index,a % (IQR) 11 (5-20) 15 (5-30) 0.31 24 (17-40) 20 (10-30) 0.17 20 (5-40) 25 (20-40) 0.98
 Median Weiss score, n (IQR) 5 (3-7) 5 (4-7) 0.44 5 (4-6) 5 (3-6) 0.1 5 (3-6) 5 (4-6) 0.88
 Median S-GRAS score, n (IQR) 2 (2-3) 3 (1-3) 0.25 3 (3-5) 3 (2-4) 0.49 3 (1-6) 4 (2-5) 0.87
Medical treatment, n (%)
 Mitotane yesb 112 (62.6) 380 (70.8) 0.31 25 (89.3) 70 (83.3) 0.23 7 (70) 25 (83.3) 0.36
 In adjuvant setting 82 (45.8) 194 (36.1) 0.001 19 (67.9) 43 (51.1) 0.006 4 (40) 8 (26.7) 0.14
 In advanced disease 45 (25.1) 344 (64.1) 10 (35.7) 41 (48.8) 6 (60) 19 (63.3)
 Chemotherapy yes 40 (22.3) 227 (42.3) 0.001 12 (42.9) 48 (57.1) 0.39 6 (60) 20 (66.7) 0.61
 In adjuvant setting 2 (1.1) 8 (0.01) 0.001 2 (7.1) 3 (3.6) 0.076 1 (10) 1 (3.3) 0.18
 In advanced disease 38 (21.2) 219 (40.7) 10 (35.7) 45 (53.6) 5 (50) 19 (63.4)
Outcome data
 Recurrence/progression yes, n (%) 77 (43.0) 423 (78.8) 0.001 23 (82.1) 72 (85.7) 0.65 8 (80) 27 (90) 0.41
 Median months until recurrence/progression (IQR) 102.9 (63.5-142.4) 18.4 (15.8-20.9) 0.001 16.3 (1.5-31.1) 9.6 (6.5-12.7) 0.33 6.8 (1.3-18.3) 6.7 (1.6-11.6) 0.59
 Median overall survival, months (IQR) 261.6 (102.5-420.7) 80.3 (61.6-99.1) 0.001 53.4 (26.1-80.5) 38.5 (22.9-54.1) 0.53 29.6 (8.3-51.6) 32.4 (15.3-49.5) 0.36
 Dead yes, n (%) 30 (16.8) 272 (50.7) 0.001 14 (50) 52 (61.9) 0.27 5 (50) 20 (66.7) 0.35
 Median time of follow-up, months (IQR)c 53.8.(22.9-89.5) 69.3 (26.2-121.8) 0.024 38.2 (12.9-66.5) 58.9 (17.2-132.5) 0.34 82.1 (3.8-126.7) 19.3 (7.2-94.7) 0.61
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ACC, adrenal cortical carcinoma; ENSAT, European Network for the Study of Adrenal Tumours; IQR, interquartile range; NA, not available; ND, not done.

a

Of the primary tumour.

b

Several patients have received mitotane both in an adjuvant setting and later in advanced disease.

c

In patients still alive.

A total of 179 patients with oncocytic ACC were compared with 537 patients with conventional ACC. There were no statistically significant differences in age, sex, hormone excess, ENSAT stage, resection status, tumour size, Ki67 index, Weiss score, or S-GRAS score. Oncocytic tumours were treated slightly more often with adjuvant mitotane, whereas conventional ACCs were significantly more often treated with mitotane in advanced disease (P < 0.001) (Table 3). Furthermore, conventional ACCs were treated more frequently with chemotherapy especially in advanced disease (P < 0.001).

RFS was investigated in 127 patients with oncocytic ACC and matched to 381 patients with conventional ACC. RFS occurred significantly more frequently in conventional (75%) compared with oncocytic ACC (38%) (P < 0.001), with a significant longer time to progression in oncocytic ACC (104 versus 24 months, P < 0.001) (Figure 2).

Figure 2.

Figure 2

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Kaplan-Meier survival curves for the whole cohort. Kaplan–Meier curves for matched oncocytic (A), myxoid (B), and sarcomatoid (C) adrenal cortical carcinoma (ACC) with conventional ACC for recurrence-free survival (RFS) and overall survival (OS).

When we express the results as hazard ratios (HRs) using univariate Cox regression analyses, RFS was significantly longer in oncocytic ACC compared with conventional ACC [RFS HR 0.41, 95% confidence interval (CI) 0.29-0.55, P < 0.001]. Myxoid and sarcomatoid ACCs showed similar outcomes for RFS in comparison to conventional ACC (myxoid RFS HR 0.96, 95% CI 0.49-1.86, P = 0.90; sarcomatoid RFS HR 0.96, 95% CI 0.36-2.84, P = 0.94).

OS was evaluated for all 179 oncocytic ACCs matched to 537 conventional ACCs. OS was also significantly longer in oncocytic ACC compared with the matched conventional ACC (261 versus 80 months, P < 0.001), with significantly fewer patients who had died at last follow-up (16% versus 50%) (Figure 2). However, this was not the case in myxoid and sarcomatoid ACC when matched with conventional ACC (Figure 2).

Univariate Cox regression analyses showed a significantly longer OS in oncocytic ACC compared with conventional ACC (OS HR 0.35, 95% CI 0.24-0.52, P < 0.001). Myxoid and sarcomatoid ACC showed similar outcomes for OS in comparison to conventional ACC (myxoid OS HR 1.29, 95% CI 0.54-3.11, P = 0.56; sarcomatoid OS HR 0.65, 95% CI 0.16-2.63, P = 0.54).

Treatment efficacy of adjuvant mitotane therapy

Oncocytic tumours were treated slightly more often with adjuvant mitotane (45.8% versus 36.1%, P = 0.007). However, there was no difference in RFS and OS among patients treated with adjuvant mitotane between oncocytic (n = 82) and conventional ACC (n = 194) in propensity score matching (HR for RFS 0.66, 95% CI 0.43-1.02, P = 0.06 and for OS 0.65, 95% CI 0.32-1.41, P = 0.19).

Treatment efficacy of mitotane monotherapy and chemotherapy in advanced disease

Treatment with mitotane monotherapy in advanced disease also showed similar results (oncocytic n = 11 versus conventional ACC n = 144: HR for OS 1.59, 95% CI 0.76-3.45, P = 0.98). Of the 11 patients with oncocytic ACC, 2 experienced partial response and 9 had immediate disease progression.

Currently, the most frequently used first-line chemotherapy in ACC is etoposide, doxorubicin, cisplatin, and mitotane (EDP-M)3,55 or other platinum-based chemotherapy in combination with mitotane. In our series, 37 patients with oncocytic ACC were treated with this therapy for advanced disease. Among them, 3 patients experienced complete response, 3 partial response, 9 stable disease, and 21 progressive disease. Of note, one patient with a complete response did not have a recurrence until the last follow-up after 46.2 months. The overall median time to progression was 19 months (4-46 months). Ten and five patients with myxoid and sarcomatoid ACC, respectively, were also treated with platinum-based regimens. The OR rates were comparable to conventional ACC (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2026.106092). Next, we compared progression-free survival and OS between 37 patients with advanced oncocytic ACC and 298 patients with conventional ACC after starting platinum-based chemotherapy. Progression-free survival was statistically longer in oncocytic ACC versus conventional ACC (11.0 versus 7.7 months; HR 0.53, 95% CI 0.37-0.77, P = 0.01), but OS was not (75.9 versus 40.5 months; HR 0.69, 95% CI 0.43-1.11, P = 0.13).

For myxoid and sarcomatoid ACC, median progression-free survival was 9.4 and 6.8 months, respectively, and OS was 77.2 and 21.4 months.

Treatment with other chemotherapy regimens was used only in individual cases. One oncocytic patient was treated with streptozotocin, resulting in progressive disease, and was later treated with gemcitabine/capecitabine, resulting in stable disease. One patient with myxoid ACC showed stable disease under therapy with streptozotocin.

Discussion

This retrospective multicentre cohort study represents by far the largest cohort of patients with rare ACC subtypes compared with conventional ACC. Our data suggest that oncocytic histology is associated with a positive impact on prolonged RFS and OS in comparison to conventional ACC. This difference is also visible in the 1 : 3 matched propensity score analyses. Within this cohort of matched patients, 38% with oncocytic ACC developed recurrence compared with 74% of patients with conventional ACC. RFS (univariate Cox regression HR 0.41, 95% CI 0.29-0.55, P < 0.001) was significantly different. Similarly, OS was significantly longer in the oncocytic variant (HR 0.35, 95% CI 0.24-0.52, P < 0.001).

To date, there are controversial results regarding the better outcome of oncocytic ACC. Renaudin et al. compared 43 patients with oncocytic adrenal cortical tumours (28 oncocytic ACC) with 37 patients with conventional ACC and found improved OS (92% versus 56% at 2 years) in patients with oncocytic histology compared with patients with conventional ACC.10 Another recently published study indicated that oncocytic histology has a more indolent biology compared with conventional ACC, with longer reported median time to recurrence and a tendency toward longer OS in oncocytic ACC.44 Another study by Prinzi et al. compared 44 oncocytic ACC with 145 conventional ACC. After adjusting in a multivariate analysis, oncocytic ACC appeared to have a more indolent clinical course and a better prognosis than conventional ACC.49

In contrast, Shirali et al. showed that oncocytic histology does not confer indolent biological behaviour. Rather, patients with oncocytic ACC have similar RFS and OS compared with patients with conventional ACC in a 2 : 1 matched analysis.43

Taken together, our findings are in line with the reported improved outcomes in patients with oncocytic ACC.10,44,49 The different results reported by Shirali et al. could be explained by the lack of matching oncocytic patients to conventional patients for several clinical criteria.43

We could demonstrate in both statistical approaches (multivariate analyses and propensity score matching) that median age <51 years, Ki67 index <10%, ENSAT stage 1 + 2, and the oncocytic variant may serve as important factors associated with longer RFS and OS in the oncocytic subgroup compared with conventional ACCs. These prognostic markers have already been investigated in several studies, indicating their important value for the estimation of prognosis in ACC.4,12,56, 57, 58 Oncocytic ACC showed a more favourable prognostic profile than conventional ACC and this possibly accounted for the improved outcomes.

In addition, we investigated treatment efficacy in the oncocytic variant. Our analyses suggest that the systemic therapies recommended for conventional ACC by both ACC guidelines3,59 (e.g. mitotane monotherapy as well as platinum-based chemotherapy in combination with mitotane) seemed to have similar efficacy compared with mitotane and platinum-based chemotherapy in oncocytic ACC. This is a very important message from a clinical perspective, because previously clinicians were uncertain about this issue as there was no information on whether these therapies, despite their adverse effects, really help patients with oncocytic ACC.

Another aim of the study was to compare the outcomes of myxoid and sarcomatoid ACC. Until now, most of the published studies are case reports indicating a similar prognosis for myxoid ACC,20, 21, 22 but a more aggressive behaviour in sarcomatoid ACC.27 Due to the limited number of patients with myxoid and sarcomatoid ACC in our cohort, analyses for these ultrarare subtypes are statistically underpowered. Therefore, results regarding RFS and OS in myxoid and sarcomatoid ACC should be interpreted with caution and considered exploratory in nature. While no significant differences compared with conventional ACC were observed in our cohort, these findings are descriptive and hypothesis-generating rather than conclusive.

Limitations of this study include information, referral, and selection bias due to its retrospective design, the relatively small sample size of the myxoid and sarcomatoid ACC groups, and the low number of patients receiving mitotane monotherapy in oncocytic ACC. Moreover, we could not include all prognostic factors such as Ki-67 index in the propensity score matching due to missing clinical data. Other limitations include heterogeneity in the treatment and follow-up protocols as well as variable duration of follow-up. The conventional ACC group originated from a single centre; however, we did not observe any differences in patients with oncocytic ACC from this centre compared with other centres. However, this study currently represents the best data available due to the absence of published data with a higher number of patients with different subtypes. Another strength of this study is the multicentre design accounting for differences in practice.

Moreover, adoption of the LWB criteria7 was included in the histopathological diagnosis of oncocytic ACC at different time points in all the participating centres questioning differences in the correct histological diagnosis between time periods. However, the histological review of all oncocytic cases by adrenal expert pathologists in the participating centres allowed us to verify the cases and use only correctly diagnosed oncocytic ACC.

Conclusion

We present a multicentre study examining the clinicopathological behaviour of rare ACC subtypes, especially oncocytic ACC, in comparison to a large cohort of conventional ACC. Oncocytic ACCs are more often diagnosed with a lower ENSAT stage and, due to this fact, also have a higher rate of complete resection. However, after matching also for the ENSAT stage, oncocytic ACC still had a significantly longer RFS and OS compared with conventional ACC, leading to the conclusion that the oncocytic variant is in favour of a longer RFS and OS.

However, despite the more favourable prognosis and longer time to recurrence, recurrences still occurred in a substantial proportion of patients. Therefore, oncocytic histology alone does not justify changes in surveillance strategies, which should continue to be guided by established risk factors such as ENSAT stage, resection status, and Ki67 index. Importantly, we observed no relevant differences in the efficacy of adjuvant mitotane or mitotane monotherapy or platinum-based chemotherapy in advanced disease. Thus, the oncocytic subtype cannot currently serve as a decision criterion for or against adjuvant treatment, but should rather be regarded as an additional favourable prognostic factor. In addition, platinum-based chemotherapy is also effective in oncocytic ACC.

In contrast to the robust and consistent findings observed for oncocytic ACC, conclusions regarding myxoid and sarcomatoid ACC are limited by the small sample size. However, until now, there is no evidence that the rare ACC subtypes respond very differently from conventional ACC.

Acknowledgements

This study was made possible by the ACC database of the European Network for the Study of Adrenal Tumours (ENSAT) and RedCap for data collection. We are thankful for the continuous help in data documentation from Michaela Haaf.

Funding

This work was supported by the Clinician Scientist programme RISE funded by the Else Kröner-Fresenius-Stiftung (no grant number), the Eva Luise und Horst Köhler Stiftung (no grant number), and the German Research Foundation (DFG) project 314061271 (TRR-CRC 205, no grant number), and the European Reference networks Endo-ERN and EuRanCan (no grant number). This article is based upon work from EU COST Action CA20122 Harmonisation, supported by COST.

Disclosure

SP and OK received speaker honoraria from HRA Rare Diseases. All other authors have declared no conflicts of interest.

Data sharing

ACC is an ultrarare disease and patient privacy is important. However, we are committed to sharing data with all qualified external researchers. Requests have to be sent to the corresponding author. All data provided are anonymised to respect the privacy of the patients.

Supplementary data

Supplementary Table S1
mmc1.docx (15.5KB, docx)
Supplementary Table S2
mmc2.docx (18.3KB, docx)
Supplementary Table S3
mmc3.docx (13.9KB, docx)
Supplementary Figure S1
mmc4.pptx (32.4KB, pptx)

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Associated Data

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Supplementary Materials

Supplementary Table S1
mmc1.docx (15.5KB, docx)
Supplementary Table S2
mmc2.docx (18.3KB, docx)
Supplementary Table S3
mmc3.docx (13.9KB, docx)
Supplementary Figure S1
mmc4.pptx (32.4KB, pptx)

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