Radiol Oncol 2025; 59(1): 121-131. doi: 10.2478/raon-2025-0013 121 research article Management of adrenocortical carcinoma in Slovenia: a real-life analysis of histopathologic markers, treatment patterns, prognostic factors, and survival Urska Bokal1, Jera Jeruc2, Tomaz Kocjan3,4, Metka Volavsek2, Janja Jerebic5, Matej Rakusa 3,4, Marina Mencinger1,4 1 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia 4 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 5 Department of Methodology, Faculty of Organizational Sciences, University of Maribor, Kranj, Slovenia Radiol Oncol 2025; 59(1): 121-131. Received 5 May 2024 Accepted 5 November 2024 Correspondence to: Assist. Marina Mencinger, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: mmencinger@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Adrenocortical carcinoma (ACC) is a rare cancer that presents significant diagnostic and therapeutic challenges. We analyzed the management and estimated survival of ACC patients in Slovenia over a 17-year period. Patients and methods. Patients registered in the National Cancer Registry and treated from 2000 to 2017 were included. The survival and prognostic factors were assessed using the Kaplan-Meier method and Cox regression, respectively. Results. Forty-eight patients were included in our analysis. At the time of diagnosis, 6%, 42%, 25% and 27% had stage according European Network for the Study of Adrenal Tumors (ENSAT) I, II, III and IV, respectively. Adjuvant treatment with mitotane was assigned to 18 of 34 potentially eligible patients. High-risk patients treated with adjuvant mitotane showed a reduced probability of death, although the difference was not statistically significant. Relapses had numeri- cally higher rate of R1 resection and higher Ki67. Eleven patients underwent first-line therapy with etoposide, doxo- rubicin, cisplatin and mitotane (EDP-M). Their median progression-free survival was 4.4 months. The median overall survival of entire cohort was 28.9 and the median disease-specific survival (DSS) was 36.2 months. The 5-year DSS rate of ENSAT I, II, III and IV were 100%, 56%, 50% and 0%, respectively. The prognostic value of ENSAT stage and Helsinki score regarding overall survival was confirmed with the multivariate analysis. Conclusions. The 5-year DSS of our ENSAT II patients was worse than reported in contemporary cohorts. Suboptimal surgery and inconsistent adjuvant therapy with mitotane might have contributed to this outcome. Better outcomes of this rare disease might be accomplished with dedicated teams including various specialties, working towards optimal staging, diagnostic and therapeutic measures. Key words: adrenocortical carcinoma; Helsinki score; ENSAT stage; systemic treatment; survival; prognostic factors Introduction Adrenocortical carcinoma (ACC) is an aggressive orphan tumour. The annual incidence is around two cases per million people.1 The postoperative disease-free survival rate at five years is less than 50% and the 5-year survival rate for metastatic dis- ease worldwide remains dismal.2 About 50–60% of Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia122 patients with ACC have clinical hormone excess. In most cases, hypercortisolism (Cushing’s syn- drome) and/or virilisation syndrome due to andro- gen secretion are observed.3 As clinical, laboratory, and imaging features of ACC overlap with other benign and primary or secondary malignant adrenal tumours, the final diagnosis and malignant potential of an adrenal lesion depends largely on sophisticated histo- pathologic analysis of the surgical specimen. To fa- cilitate and standardize the diagnosis of ACC, sev- eral multiparametric scoring systems have been developed based on combined histopathological features, such as the Weiss score and the Helsinki score.4 The Weiss score considers nine histopatho- logic parameters and remains one of the most used scoring systems in clinical practice to classify con- ventional ACC in adults.5 A more recently devel- oped score, the Helsinki score, focuses on a combi- nation of the Ki67 proliferation index, mitotic rate, and the presence of necrosis. It can be used not on- ly for the diagnosis of conventional ACC, but also for oncocytic and myxoid variants.6 Two staging systems have been also proposed: TNM staging, which was revised in 2017 (AJCC cancer staging7), and the staging system by the European Network for the Study of Adrenal Tumors (ENSAT) in 2009.8 According to current clinical practice guide- lines, all patients with ACC and a high risk of re- currence after surgery (ENSAT stage III, R1 resec- tion or Ki67 >10%) should receive adjuvant treat- ment with mitotane.3 Recently published results of the ADIUVO trial did not support adjuvant treatment with mitotane in patients with low-in- termediate risk of recurrence (ENSAT stage I-III, R0 resection and Ki67 ≤ 10%).9 Only one phase III clinical trial (FIRM-ACT) was conducted in pa- tients with ACC. In this trial, etoposide, doxoru- bicin, and cisplatin (EDP) plus mitotane resulted in higher response rates and longer progression-free survival than streptozocin plus mitotane as first- line therapy, although there was no significant difference in overall survival.10 Recently, immune check point inhibitors and cabozantinib have been used successfully in some patients with ACC.11,12 Other treatment options are experimental at best.13 Locoregional therapies are recommended for slowly progressive oligometastatic disease or when a sustained response to systemic therapy has been achieved. In addition to surgery, there are other options such as radiotherapy, radiofrequency abla- tion and chemoembolization.3,14 We performed a retrospective analysis includ- ing histopathologic assessment of primary tu- mours and metastases, systemic treatment pat- terns, and outcomes of our patients with ACC over nearly two decades (2000-2017). In addition, we identified factors influencing survival. Patients and methods We conducted a retrospective cross-sectional study including all adult patients who were diagnosed with ACC from year 2000 to 2017 and were treated at the University Medical Centre Ljubljana and the Institute of Oncology Ljubljana. The patient list was taken from the National Cancer Registry. The study protocol was approved by the Review Board and Committee for the Medical Ethics of the Institute of Oncology in Ljubljana (ERIDEK - 0024/2020). A flowchart detailing the diagnostics and treatment decision-making process is shown in Figure 1. We used patients’ medical records to collect their demographic and clinical parameters, data on ENSAT stage at diagnosis, tumour size (defined as the largest diameter in axial plane), biochemically confirmed hormone hypersecretion, surgical treat- Endocrinology: hormonal work-up, imaging MTB: endocrinologist, radiotherapist, urologist, medical oncologist Clinical presentation or incidental imaging finding suggesting ACC Evaluation for adjuvant mitotane and radiotherapy, local surgery/ablative methods, systemic therapy Follow-up endocrinologist/medical oncologist MTB-multidisciplinary tumour Surgery Biopsy Histopathology Stage IV Stage I-III Primary or relapse M1 Locally advanced, high risk based on guidelines FIGURE 1. A patient flowchart describing the process of diagnostics and treatment decision-making. ACC = adrenocortical carcinoma; MTB = multidisciplinary tumour board; M1 = metastatic disease Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 123 ment of the primary tumour, status of resection margins, adjuvant radiotherapy and adjuvant mi- totane treatment. We explored options for the first, the second and the third line of systemic treatment. Survival analyses and tests for prognostic factors were performed for the entire cohort. In accordance with our sample size, we chose to determine the prognostic significance of three variables: ENSAT stage (I and II versus III and IV), Helsinki score and hypercortisolism (present versus absent). The prognostic value of adjuvant mitotane treatment was analysed for the high-risk patients.3 In addi- tion, the prognostic value of the Ki67 index in me- tachronous metastasis or local recurrence (20 or more versus less than 20) was tested in univariate analysis. The cut-off value of 20 was used in anal- ogy to the cut-off values for primary tumours.15,16 Two additional assessments were carried out. First, data on local treatment options for meta- static/locally recurrent disease were analysed in detail. Several survival parameters were calcu- lated in patients who underwent surgery for local recurrence/oligometastatic disease. The median treatment-free interval (mTFI) was defined as the time from diagnosis of ACC to resection of the first metachronous metastasis. The median progres- sion-free survival (mPFS) was defined as the time from the local therapy of the first metastasis to the systemic disease progression or death. The median overall survival of this cohort (mOS) was defined as the time from diagnosis of ACC to death. Second, two experienced pathologists (MV and JJ) reviewed all available archival histologic tissue samples of primary tumours and metastases of the included patients. If multiple metastases or local recurrences were available, only the one that had been histologically analysed first was revised. The Weiss scoring system was used in all adrenalecto- my specimens except for the two patients with the oncocytic variant of ACC in which Weiss system tends to overdiagnose malignancy and Lin-Weiss- Bisceglia criteria are applied instead.17 The Weiss system was only used to evaluate adrenalectomy specimens, as it is not possible to perform the re- quired assessment of venous or capsular invasion in other types of specimens (e.g. needle biopsy, metastasis, excision of recurrent disease). The Helsinki index and the Ki67 proliferation index were determined using visual estimation method.18 Immunohistochemistry for Ki67 anti- gen (clone MIB-1, Dako, 1/50, UltraView) was per- formed using a Benchmark XT Ventana system according to manufacturer’s instructions. The cor- relation between the Weiss and the Helsinki score of the primary tumours was investigated. The Ki67 index and the Helsinki score of both specimens FIGURE 2. Our cohort according to European Network for the Study of Adrenal Tumors (ENSAT) stage, adjuvant mitotane treatment, relapses and different lines of systemic treatment. ACC = adrenocortical carcinoma; ST = systemic treatment Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia124 were compared in patients in whom the tissue from both, the primary tumour and the first local recurrence or metastasis was available. Statistical analyses Data for continuous variables were presented as median and range and for categorical data as fre- quencies and percentages. The cut-off date for the survival analysis was October 15, 2020. Survival outcomes were calculated using Kaplan-Meier method with 95% confidence intervals and pre- dictors of survival were calculated using Cox pro- portional hazards regression models. The p-values shown are two sided and the p-value < 0.05 was considered statistically significant. The calculations were performed using the statistic software pack- age IBM SPSS 28.0. Correlation between Weiss and Helsinki score of primary tumours was investigat- ed with Spearman’s rank correlation coefficient test. To further explore the prognostic power of Helsinki score receiver operating characteristic (ROC) analysis was done. Area under the ROC curve (AUC) was calculated to assess the ability of Helsinki score to differentiate between “alive” versus “death” status. The cut-off value of Helsinki score to differentiate between different prognostic groups was determined based on maximizing the Youden index in the context of the ROC curve. Results Patients’ characteristics Forty-nine adult patients were diagnosed with ACC at our two centres during the studied period (2000–2017). During histologic revision one patient was diagnosed with adenoma instead of ACC and was excluded from the analysis. Characteristics of all analysed patients and of the 20 patients who re- lapsed after radical surgery are shown in Table 1. One patient with ENSAT stage III was not treated with radical surgery as the tumour was considered inoperable. Figure 2 shows our cohort according to ENSAT stage, adjuvant mitotane treatment, relapses and different lines of systemic treatment. Adjuvant mitotane treatment Thirty-four patients, who were classified as ENSAT stage I-III underwent surgical removal of the prima- ry tumour and could have been considered eligible for adjuvant mitotane. However, 12 patients (35.3%, median age 49.5 years; 7 females), including 6 pa- tients at high risk of recurrence after surgery (Ki67 >10%3); of whom three were classified as ENSAT stage II and three as stage III, were not started on this treatment. Relevant data was absent for further 4 patients (11.8%). The remaining 18 patients (52.9%, median age 63 years; 9 females,) received mitotane. Half of the treated subgroup (or 9 patients) were classified as ENSAT stage II, 38.9% (or 7) as stage III, and 11.1% (or 2) as stage I. Ki67 was > 10% in 14 of these patients (77.8%) with missing data for one patient in ENSAT stage III. Collectively, only two patients at low/intermediate risk of recurrence after surgery (R0, Ki67 ≤ 10%3; classified as ENSAT stage I and stage II), received mitotane. Two patients were followed at another institu- tion, so further data about mitotane treatment was available for 16 patients. Median time from sur- gery of primary tumour to start of adjuvant mito- tane was 26.5 (range 6–126) days, while median du- ration of treatment was 17.4 (3–73) months with the median daily mitotane dose of 2750 (500 – 7000) mg. All patients were on concurrent hydrocorti- sone replacement therapy with median daily dose of 40 (15–45) mg. Three patients (18.7%) progressed when on mitotane after median time of 30 (10–31) months of treatment and one patient died of meta- static breast cancer in the 11th month of adjuvant mitotane treatment. All discontinuations of mito- tane during adjuvant treatment were permanent. Reason for stopping were adverse effects: gastro- intestinal in 2 (25.0%), hepatic in 2 (25.0%) neuro- cognitive in 1 (12.5%) and other in 3 (37.5%) cases. Data on mitotane plasma concentrations were not obtainable for most patients, so they were not in- cluded in the analysis. High-risk patients that re- ceived adjuvant mitotane had lower risk of death (HR 0.614, 95% CI 0.207-1.820), but the difference was not statistically significant (p = 0.379). Adjuvant radiotherapy Thirty-four patients classified as ENSAT stage I-III underwent surgical removal of the primary tu- mour. Of these 34, 16 had either R1 resection or/ and ENSAT stage III disease. One of these 16 pa- tients had both ENSAT III and R1 resection, 11 had ENSAT III and 4 had R1. Finally, only three of them received adjuvant radiotherapy (RT): one with R1 resection, one with ENSAT III and one with both criteria. All other potential candidates from this group did not receive adjuvant RT (one of them due to treatment refusal); but two other patients without criteria did. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 125 Systemic treatment regimens for inoperable locally advanced or metastatic disease Thirty-four out of 48 patients had inoperable lo- cally advanced or metastatic disease, either at the time of the primary diagnosis or recurring after surgery. Nine patients were referred to palliative care only. First-line systemic treatment regimens for the remaining 25 patients are listed in Table 2. The median age of 11 patients who were treat- ed with standard first-line chemotherapy (EDP- mitotane) was 56 years (range 29–70). Their perfor- mance status was 0 in 6 patients (54%), 1 in 4 pa- tients (36%) and 2 in 1 patient (9%). Median number of cycles received was 5 (range 2–7). The mPFS was 4.4 months (95% CI 1.5–7.3) and the mOS was 15.8 months (95% CI 7.7–23.8). Two patients achieved partial response (PR), 6 patients had stable disease (SD), and 3 patients had progressive disease (PD). There were no complete responses. The patient who received treatment with dac- arbazine, cyclophosphamide and vincristine were initially diagnosed with pheochromocytoma, but histologic revision from a highly specialized cen- tre confirmed the diagnosis of ACC. All 25 patients treated with first-line therapy progressed during the therapy or follow-up pe- riod; among them, 9 (36%) received 2nd line sys- temic treatment, which is listed in Table 3 together with responses achieved. Five patients who received second line therapy with gemcitabine and capecitabine had median number of 2.5 cycles (range 2-5), median progres- sion free survival 2.3 months (95% CI 1.5-3.1) and median overall survival 10.0 months (95% CI 1.9– 18.1). Third line therapy was prescribed to 4 patients: reintroduction of gemcitabine - capecitabine, met- ronomic therapy with cyclophosphamide, tha- lidomide plus mitotane, all of whom progressed. One patient received radionuclide therapy with 131I-iodometomidate in a highly specialised centre in Würzburg, Germany, and had survived for 8 months after referral. Survival rate of ENSAT stage I, II, III and IV The 5-year overall survival (OS) of patients with ENSAT stage I, II, III and IV was 100%, 50%, 50% and 0%. If stages I/II and III/IV were grouped to- gether the 5-year OS was 56.5% and 24%. The 5-year disease specific survival (DSS) was 100%, TABLE 1. Characteristics of all analysed patients and of the patients with European Network for the Study of Adrenal Tumors (ENSAT) I-III that relapsed after surgery with curative intent Characteristics All included N = 48 (%) Relapsed N = 20 (%) Age: median (range); years 56.6 (21–82) 54.0 (21–72) Sex Male 21 (44) 11 (55) Female 27 (56) 9 (45) ENSAT stage at diagnosis I 3 (6) 0 II 20 (42) 12 (60) III 12 (25) 8 (40) IV 13 (27) N/R Tumour size: median (range), cm 12 (4–30) 12.5 (5–30) Unknown 6 2 Hormone secretion Yes – GC* 17 (35) 5 (25) Yes – O 8 (17) 4 (20) No 20 (42) 11 (55) Unknown 3 (6) / Weiss score (median, range) 6 (4–9) 7 (5–9) N/D+ 15 1 Ki67 score** (median, range) 20 (1–70) 24 (8–60) N/D° 9 1 Helsinki score** (median, range) 28 (1–78) 31 (16–68) N/D° 9 1 Resection margins of patients stage I –III treated with curative surgery R0 26 (76) 17 (85) R1 5 (15) 3 (15) Rx 3 (9) / GC = glucocorticoids; O = other; N/D = not determined; N/R = not relevant; * = isolated or in combination with other hormones; ** = of primary tumour; + due to oncocytic variant (2), unavailability of tissue samples (3): primary not operated - 1 patient; tissue not available at our institutions - 2 patients), only fine needle (6) or core needle biopsy (4) of primary tumour or metastases; ° due to unavailability of tissue samples (3) or only fine needle biopsy of primary tumour or metastases (6) TABLE 2. First-line systemic treatment regimens for inoperable locally advanced or metastatic disease Treatment regimen Patients (N) EDP-mitotane 11 mitotane (+/- local therapy) 11 etoposide + carboplatin 1 dacarbazine + cyclophosphamide + vincristine 1 tamoxifen 1 EDP = etoposide, doxorubicin and cisplatin 56%, 50% and 0%, respectively. The 5-year OS of patients with ENSAT stage I-III who were diag- nosed before year 2010 was 61.9% and of patients with ENSAT stage I-III who were diagnosed after the year 2010 was 42.9%; the difference was not Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia126 statistically significant (p = 0.132). The mOS of pa- tients with ENSAT stage IV who were diagnosed before and after year 2010 was 1.5 months (95% CI 0.00 – 3.89) and 8.6 months (95% CI 0.42 – 16.73), respectively. This difference was also not statisti- cally significant (p = 0.338). Survival analysis of the whole cohort and prognostic factors The median follow-up of the cohort was 30.0 months; 36 (75%) patients died. The mOS was 28.9 months (95% CI 10.25-47.51). Three patients died for other reasons (not ACC). Median DSS was 36.2 months (95% CI 11.8-60.6). In univariate analysis significant impact of ENSAT stage III/ IV versus I/II (HR 2.989; 95% CI 1.483-6.023; p = 0.002) and Helsinki score (HR for each additional unit of Helsinki score 1.02; 95% CI 1.003–1.042; p = 0.021) on OS was confirmed, but not of hypercor- tisolism (HR 1.523; 95% CI 0.772–3.006; p = 0.225). Multivariate analysis confirmed the prognostic value of the ENSAT stage (HR 2.796; CI 95% 1.258– 6.212; p = 0.012) and Helsinki score (HR 1.027; 95% CI: 1.005–1.049; p = 0.015). Kaplan-Meier curves of OS according to ENSAT stage groups are shown in Figure 3. Fourteen of 34 patients who were operated on ACC ENSAT stage I-III remained disease free. Two patients progressed more than 5 years after sur- gery on primary tumour: 10 years and 9 months with local recurrence treated with surgery and RT, being alive at the time of the data cut-off; 5 years and 7 months with inoperable local recurrence, later further systemic progression and death. To further explore the prognostic power of Helsinki score ROC analysis was performed which was statistically significant (overall model quality 0.55) with AUC 0.761 (95% CI 0.551-0.971). The cut- off value for Helsinki score determining two prog- nostically different groups was 19.5. Locoregional treatment for primary metastatic or relapsing disease Only 6 patients from our cohort were treated for local recurrence or metastatic disease with local treatment methods. As a rule, surgery was per- formed; which was combined with radiofrequen- cy ablation (RFA) in only one patient. Patients who received only palliative radiotherapy were not in- cluded in this subgroup analysis. Most patients (5 out of 6 or 83%) had metachronous metastases that had occurred three months or more after surgery for the primary tumour.19 One patient had solitary synchronous liver metastasis that was resected concomitantly with the primary tumour. In anoth- er patient, surgery was performed multiple times and combined in the third session with RFA of two liver metastases and one thoracic metastasis that had spread through the diaphragm. Overall, local recurrences were resected in three (50%) patients, liver metastases in two (33%) patients and lung and vertebral metastases in one (16%) patient. Four patients: two with local recur- rence, one with liver metastasis and one after right pneumonectomy of multiple lung metastases re- ceived RT after the local surgery. The mTFI was 32.1 months (95% CI 17.6–131.3). The mPFS was 7.29 months (95% CI 0.00-61.2) and mOS was 65.5 months (95% CI 9.4-121.55). The two patients who received RT after surgery for local recurrence both remained disease-free. TABLE 3. Second line treatment regimens Treatment Patients (N) Response gemcitabine + capecitabine +/- mitotane 5 SD: 1PD: 4 EDP-mitotane 1 PR pembrolizumab 1 SD dacarbazine + capecitabine + imatinib 1 PD vinblastine + interferon alpha-2a 1 PD EDP = etoposide, doxorubicin and cisplatin; SD = stable disease, PD = progressive disease, PR = partial response FIGURE 3. Kaplan-Meier curves of overall survival according to European Network for the Study of Adrenal Tumors (ENSAT) stage. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 127 Histopathologic features Histopathologic analysis was possible in 40 of our patients where the diagnosis was confirmed histo- logically by either resection or core needle biopsy of the primary tumour or metastases. In six pa- tients, the primary tumour or metastases were on- ly verified cytologically and in two patients adre- nalectomy was performed but no tissue was avail- able for analysis at our two institutions. Archival tissue blocks of formalin-fixed paraffin-embedded (FFPE) tissue for analysis were obtained after ad- renalectomy (35: from 34 patients ENSAT stage I– III and one patient ENSAT stage IV), core needle biopsy of primary tumours (4) or metastatic depos- its (2) and resection of the first local recurrences or metastases (10). Histologic variants of ACC in our cohort were as follows: 35 had conventional ACC, two patients had oncocytic variant, two myxoid (one of them partial myxoid and partial conventional type), and one sarcomatoid variant. Survival of patients with pure myxoid (3.9 months) and sarcomatoid (6.5 months) histologic variant was less than the medium overall survival of the whole cohort (28.9 months). Both patients with oncocytic variant and the patient with partial myxoid variant (ENSAT stage I) were progression-free at the time of the data cut-off. As far as primary tumours were concerned, Weiss score was determined in 33 patients and Ki67 proliferation index and Helsinki score in samples from 39 patients. These data are shown in Table 1. In 12 metastatic/recurrent samples, the median Ki67 index was 27.5 (range 11–60) and the median Helsinki score was 35.5 (range 19–68). There was no correlation between Weiss and Helsinki scores of primary tumours as the Spearman’s correlation coefficient was - 0.092 (p = 0.612). In 11 patients, the tissue from resected primary tumours as well as from the first metastasis/local recurrence was available for investigation. Table 4 shows the com- parison between their Ki67 index and Helsinki score. Patients from 1 to 9 had local recurrence or me- tachronous metastasis. In the univariate analysis of this cohort those with Ki67 index of the local recurrence/metastasis of 20 or more (N = 6) had a statistically significantly shorter survival from the diagnosis of being metastatic/recurrent than the others (N = 3), HR 1.12 (95% CI 1.01 – 1.25), p = 0.033. Multivariate analysis was not performed due to small sample size. Discussion We have confirmed the poor prognosis of patients with ACC treated in routine clinical practice. In al- most half of our patients, the tumour was confined to the adrenal gland and less than one third had primary metastatic disease, which differs from the stage distribution in historic reports. In an older series of 42 patients diagnosed with ACC at Roswell Park Memorial Institute between 1929 and 1977, only 7% of patients had tumour confined to the adrenal gland, while 41% had locally advanced disease and 52% had metastatic disease.20 Wooten et al. reviewed data on ACC patients described in the English literature between 1952 and 1992 and found that only 31.8% of 608 patients had tumours confined to the adrenal gland.21 However, in con- temporary reports from Portugal and Finland, stages were distributed similarly to our cohort, with 43% and 59% of tumours confined to the adrenal gland, respectively.22,23 The observed con- temporary shift in ENSAT staging is likely due to earlier ACC diagnosis, resulting from better avail- ability of radiologic imaging, often performed for unrelated reasons (adrenal incidentalomas).23 In our series oncocytic and myxoid variants accounted for five percent of ACCs, while sarco- matoid variant was detected in 2.5% of all ACC included in the histopathologic analysis. The relative frequency of the variant histology is con- sistent with previously published data.4 As ex- pected, the clinical behaviour of patients with myxoid and sarcomatoid variants of ACC was TABLE 4. Ki67 proliferation index and Helsinki score shown for primary tumour (P) and first metastasis/local recurrence (M) Patient Ki67 Helsinki score P M P M 1 16 40 24 48 2 20 16 23 24 3 15 25 23 33 4 20 20 28 23 5 30 30 38 38 6 40 30 48 38 7 15 11 18 19 8 30 20 38 28 9 10 11 18 19 10 40 50 48 50 11 25 50 29 58 Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia128 worse than in patients with the classic variant and the behaviour of oncocytic ACC was better. The patient with the partial myxoid variant who was progression-free at the time of the data cut- off, was diagnosed as ENSAT stage I, which was probably the most important factor for their good prognosis. Presumably, favourable stage distribu- tion and access to systemic treatments impacted the median OS of our entire cohort (28.9 months), which is longer than observed historically (14 months).20 Five-year overall survival rate of our ENSAT stage III (50%) and IV (0%) patients is com- parable to published series from Portugal22 (56%; 0%) and Finnland23 (stage III/IV 24% for our cohort vs. 26%). On the other hand, five-year survival rate of our ENSAT stage II patients is inferior to both Portuguese (stage I/II 56.5% vs. 67%) and especially to Finnish cohort (stage I/II 96%). Worse outcome can be at least partially explained by incomplete resections24 (four patients with ENSAT stage II had R1 resection), less than optimal surgical technique by non-expert surgeon, e.g. not performing con- comitant regional lymphadenectomy (four out of five patients operated by non-urologists relapsed), and lack of adjuvant mitotane therapy (three pa- tients with stage II should receive it due to high Ki67 but did not). In addition, some of our early ENSAT stage II patients might have been misclas- sified due to suboptimal staging, e.g. performing a chest X-ray instead of a CT. A higher percentage of stage I tumours in the Finnish cohort (19% versus 6% in our cohort) might have been also partially responsible for the difference. The five-year over- all survival of our ENSAT I-III patients diagnosed after 2010 was not better than before 2010. Less favourable stage distribution without any ENSAT stage I patients diagnosed after year 2010 might have contributed to the lack of improvement. This indicates that during our observed period 2000 – 2017 there was no trend in detecting disease ear- lier; this trend was only observed in comparison to historic cohorts as discussed previously. In the Finnish cohort, 79% of patients received adjuvant mitotane therapy, which was reported as a factor associated with better survival in this study.23 Mitotane was prescribed to everybody af- ter successful surgery except in cases with a very low risk for recurrence according to an expert opinion.25 No such straight-forward reasoning was present in our cohort. Only 52.9% of the patients started therapy with mitotane, therefore, 6 patients at high risk of recurrence after surgery3 might have been inappropriately excluded from this treat- ment. The main reason for this undertreatment was a lack of clinical practice guidelines on the management of ACC3 during the observed period causing not only uncertainties in the mitotane use, but also patients’ refusal of this treatment in some cases. Interestingly, similar inconsistency was also apparent in a recent Italian national cohort study where among 134 operated ACC patients selected just for surveillance 44.4% had Ki67 > 10%.26 On the positive side, only two of our patients who were started on mitotane were at low/intermediate risk of recurrence after surgery and might have been overtreated.9 Furthermore, most of our patients started with mitotane within the ideal 6 weeks after surgery. The drug was mostly administered for at least two years, but no longer than 5 years, as recommended.3 Some patients did not follow this pattern and there were 9 permanent discon- tinuations due to adverse effects like in other co- horts.22,23 Hydrocortisone supplementation was a uniform feature of all our patients on mitotane. However, our daily hydrocortisone replacement doses (median 40 mg, range 15–45 mg) might not have been entirely sufficient, as these patients typically require 50 mg or even up to 100 mg daily due to increased hydrocortisone clearance and in- creased cortisol-binding globulin.25,27 If our high- risk patients received adjuvant mitotane, they had better survival, as it was previously shown else- where.23 A lack of statistical significance could be attributed to small size of our cohort. The most frequent combined chemotherapy used for the first line treatment was EDP-M pro- tocol, which is the suggested treatment by the guidelines3,14 according to the results of FIRM-ACT trial.10 The outcomes of our patients who received the first line EDP-M treatment in real-life clini- cal practice were comparable to the results of that trial (mPFS 4.4 months (95% CI 1.5–7.3) versus 5.0 months (95% CI 3.5–6.9), mOS 15.8 months (95% CI 7.7-23.8) versus 14.8 months (95% CI 11.3–17.1), which probably reflects the fact that only patients with a good performance status were treated in such way (mostly WHO PS 0/1 and only 1 patient WHO PS 2). Monotherapy with mitotane was used as frequently for the first line therapy as the EDP-M protocol. Among reasons for the monotherapy with mitotane were poor performance status, co- morbidities and patients’ refusal of chemotherapy. No comparison between EDP-M protocol and mi- totane monotherapy could be made since patients in the latter group were in worse general health. Further lines of treatment were poorly effective, and few patients were able to receive them (36% of patients treated with the first line and 44% of Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 129 patients treated with the second line therapy). In this setting, there is no proven systemic therapy showing improved survival in a randomised con- trolled trial. Accordingly, the selection of second- line treatment for our patients was based on small phase 2 trials or even case reports.28,29 The mOS of patients who received systemic treatment for advanced disease was 13.0 months (95% CI 5.1–20.8) which is less than the mOS of 18.7 months that was observed by the Ohio State University Comprehensive Cancer Centre be- tween years 1997 and 2016.30 In their cohort 64% of patients received the second line treatment and they also had the possibility to participate in clini- cal trials. This emphasizes the importance of col- laboration with international specialised centres when treating this rare disease.31 In our cohort the mOS of patients with ENSAT stage IV diagnosed after year 2010 is higher in comparison to those who were diagnosed until year 2010 which may reflect better systemic treatment options in the re- cent decade, although the difference is not statisti- cally significant. Two patients experienced relapse of the disease more than 5 years from surgery of the primary tumour, which supports the continu- ation of follow-up beyond 5 years as suggested by the clinical guidelines.3 Only six patients were treated with local ther- apy for relapsing/metastatic disease. Five patients had surgical resection of their solitary metastatic lesions according to the guidelines where routine use of surgery in widespread disease is not recom- mended.3 The remaining patient who underwent surgery despite several synchronous metastases died after only three months reflecting the futil- ity of the approach due to more aggressive disease. Contrary to that, the other 5 patients had a slowly progressive disease as indicated by mPFS that was 7.3 months and mTFI that was 31.1 months. Two patients had been disease-free for more than 10 years after surgery of local recurrence, which further dictates a tight follow up with an early detection of resectable local recurrence to benefit some patients. Both patients with long last- ing remission received also postoperative radia- tion. A large recent study in advanced ACC pro- vided evidence that RT can be effective.32 Importantly, only 3 out of our 5 patients who re- ceived adjuvant RT, were appropriately selected ac- cording to current guidelines. On the other hand, 9 of 13 patients classified as ENSAT stage III and/or having R1 resection were not offered adjuvant RT after surgery for a primary tumour. According to current guidelines adjuvant RT should be consid- ered on an individual basis (in addition to mito- tane) in patients with R1 or RX resection or/and in ENSAT stage III.3 Retrospective data showed that adjuvant RT can reduce the risk of local recurrence but does not prevent distant recurrences and, con- sequently, does not impact OS.32 Randomised data on the usefulness of RT after surgical resection of primary tumour and of metastases are needed. Only a single patient underwent RFA. Other locoregional methods such as stereotactic radia- tion or chemoembolization of metastases were not used. Contrary to our approach, it is currently rec- ommended to use several local therapeutic meas- ures on an individual basis in addition to surgery for advanced ACC.3 Furthermore, a recent retro- spective analysis of 106 patients supported the use of locoregional treatments to treat ACC recur- rence.33 It is reasonable to assume that close col- laboration with an interventional radiologist could have optimised palliation in a larger proportion of our patients with metastases amenable for local treatment. Not only the disease stage, but also margin- free (R0) resection, glucocorticoid excess and Ki67 proliferation marker were suggested as prognostic factors of survival.14 Due to small sample size only ENSAT stage, Helsinki score and hypercortisolism were tested as prognostic factors. In multivariant analysis, both ENSAT stage and Helsinki score predicted survival. Helsinki score was validated as a prognostic marker for ACC in several other stud- ies.6,34,35 Unlike ENSAT stage and Ki67, Helsinki score was not found to have prognostic value in a recent series of patients with ACC from Finland.23 Helsinki score includes two proliferation markers (Ki67 immunohistochemistry and mitotic count) and necrosis. While the prognostic value of prolif- eration has been validated in many studies on the Weiss parameter15,36,37,38,39, the presence of necrosis, on the other hand, has only recently been suggest- ed as the most powerful ominous factor and the best predictor of OS and DFS in ACC patients.40 No correlation between Helsinki and Weiss score was found in our cohort, which is different from the findings of another study showing strong positive correlation between these two scoring systems.41 In addition to low number of patients included in our calculation, technical issues with respect to Ki67 immunohistochemistry on archi- val samples not allowing optimal evaluation could partially explain these discrepancies. In our cohort, the cut-off value for the Helsinki score of 19.5 performed best in terms of prognos- tic stratification. In comparison, Pennanen et al. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia130 proposed a lower cut-off value of 17 to distinguish tumours with prolonged survival from rapidly progressing tumours.34 Duregon et al. used the Helsinki scores of 13 and 19 to classify patients in- to three prognostically distinct groups.6 In a more recent study, the Helsinki score of 20 was identi- fied as one of the strongest independent predictors of death, being able to distinguish tumours with prolonged survival from those with rapid progres- sion.35 In our cohort, there were not enough pa- tients with low Helsinki scores to allow stratifica- tion into three groups. Several patients with a high Helsinki score had a favourable clinical course, possibly due to relatively small tumour size, com- plete surgical resection, and good response to treatment. Based on our and similar studies, there is probably no exact cut-off value for the Helsinki score to prognosticate disease, but rather a range between 17 and 20. We did not find a general tendency towards a higher Ki67 index in metastases compared to pri- mary tumours, as it was shown by study investi- gating the Ki67 index in primary breast cancer and corresponding metastases.42 Nevertheless, previ- ously published data for primary ACC tumours15,16 and our analysis of the Ki67 index of the first local recurrence/metachronous metastasis showed that a Ki67 index < 20 might correlate with a slower pro- gression compared to Ki67 ≥ 20. There is similarity to what was demonstrated in breast cancer, where a low Ki67 index in metastasis was associated with longer survival independently of primary tumour proliferation.43 Beside TFI indicating aggressive- ness of a disease course, analysis of Ki67 in a me- tastasis may be beneficial to indicate slowly pro- gressing disease as has already been suggested in breast cancer.43 However, more data are needed to draw any firm conclusions. Our study has some limitations due to its retro- spective methodology and incomplete information from patient charts. In addition, archived FFPE material of varying quality and age, originating from different institutions had to be re-examined. Importantly, patients treated with mitotane were not compared according to their mitotane plasma concentrations due to missing data. Small sample size allowed only few prognostic factors to be test- ed. The main strength of our study is the joint ef- fort of pathologists, endocrinologists and medi- cal oncologists to comprehensively review the management of ACC in Slovenia over the last two decades. We tried to highlight the available good practices while also exposing the shortcomings. In particular, the importance of the appropriate his- topathology diagnosis and strict adherence to the clinical guidelines if available were pointed out to improve all aspects of management from expert surgery and adjuvant mitotane treatment to lo- coregional therapies. Conclusions Research on ACC is partially hampered by the rar- ity of this type of cancer. Therefore, the presented real-world data might help the clinicians to im- prove the management of this rare and often fatal disease. A multidisciplinary approach, as high- lighted here, is of paramount importance, and has already been shown to impact survival.44 Acknowledgments We are indebted to Antonela Sabati Rajić, M.D. who started to systematically collect data about our patients with ACC. We also acknowledge the help of everybody else involved in the manage- ment of our patients with ACC. References 1. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. 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