ORIGINAL ARTICLE
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Impact of en bloc extended R0 resections on oncological outcome of locally advanced adrenocortical carcinoma
Priscilla Francesca Procopio1,2 . Francesco Pennestrì1,2D . Antonio Laurino1 . Esther Diana Rossi3,4. Giovanni Schinzari5,6 . Alfredo Pontecorvi6,7 . Carmela De Crea1,2 . Marco Raffaelli1,2
Received: 22 January 2025 / Accepted: 15 April 2025 / Published online: 3 May 2025 @ The Author(s) 2025
Abstract
In locally advanced adrenocortical carcinoma (ACC) (ENSAT stage III - S-III) RO surgery, involving en bloc extended resec- tions, is the only potential curative treatment. We evaluated oncological outcomes and complications rate in S-III patients who underwent extended resection in comparison with stage I/II (S-I/II). Among 1098 adrenalectomies over 27 years (1997 -2024) in a tertiary referral center, medical records of ACC patients were reviewed, excluding stage IV and not-multivisceral resections in S-III patients. Forty-eight patients met the inclusion criteria: 6 S-I (12.5%), 36 S-II (75%) and 6 S-III (12.5%) patients. The latter patients’ cohort underwent multivisceral en bloc resections (3 total nephrectomies, one renal vein thrombectomy, one splenopancreasectomy associated with total nephrectomy, left hemicolectomy and omentectomy, one liver S6-S7-S8 resection). Open adrenalectomy was scheduled in all S-III patients. Minimally-invasive approach was scheduled in 21 (50%) S-I/II patients. Conversion to open adrenalectomy was registered in 5 out these 21 patients. Locoregional and distant disease recurrences were registered in 19% of S-I/II vs 33.3% of S-III patients and 28.6% of S-I/II vs 66.7% of S-III patients, respectively (p=0.420, p=0.064). Postoperative complications were observed in 21.4% of S-I/II patients and 16.7% of S-III patients (p=0.788). Kaplan-Meier DFS and OS curves were comparable among the two groups (p=0.255, p=0.459, respectively). After univariable analysis, hyperfunction and chemotherapy were significantly associated with locoregional disease recurrence (p=0.02, p=0.04, respectively). OS and DFS of S-III ACC patients undergoing extended en bloc R0 resections were comparable to those of S-I/II patients, without increased postoperative morbidity.
Keywords Adrenocortical carcinoma (ACC) . ENSAT Stage III . Extended multiorgan resection · Locoregional recurrence · Oncological outcome · R0 resection
Priscilla Francesca Procopio and Francesco Pennestrì are co-first authors as they equally contributed to the article.
Preliminary results of this work have been presented as oral communication at the 10th Biannual Consensus Meeting on Advanced Endocrine Malignancies, ESES Congress, Mainz, Germany, 18-20 May 2023.
☒ Francesco Pennestrì francesco.pennestri@policlinicogemelli.it
1 U.O.C. Chirurgia Endocrina E Metabolica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
2 Centro Di Ricerca in Chirurgia Delle Ghiandole Endocrine E Obesità, Università Cattolica del Sacro Cuore, Rome, Italy
3 U.O.C. Anatomia Patologica Della Testa E Collo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, del Polmone E Dell’Apparato Endocrino, Rome, Italy
4 Dipartimento Di Scienza Della Vita E Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
5 Comprehensive Cancer Center, U.O.C. Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
6 Dipartimento Di Medicina E Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
7 Endocrinologia E Diabetologia, U.O.C. Medicina Interna, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Introduction
Adrenocortical carcinoma (ACC) is a rare neoplasm, affect- ing 0.7 to 2 patients per million per year, with a dismal prog- nosis, being the second most aggressive endocrine malig- nancy behind undifferentiated thyroid cancer [1, 2].
Prognosis in ACC is mainly based on tumor stage (S), and the outcomes may be widely heterogeneous [3, 4]. In this view, the 5-years overall survival (OS) has been strictly related to ENSAT staging system, dropping from 82% (69%-99%) in S-I (≤ 5 cm) tumors to 61% (51%-69%) in S-II (> 5 cm) tumors and 50% (39%-61%) in S-III tumors (with positive lymph nodes and/or extra- adrenal tissue infiltration and/or venous thrombus in renal vein/inferior vena cava-IVC) [5-8].
Despite standardization of adjuvant treatment, progno- sis did not significantly change in the last decades [8]. This evidence may be partially explained by ACC high propensity to relapse [5]. Both locoregional and distant disease recurrence is associated to a more aggressive bio- logic behavior, thus more difficult to control [5]. As a con- sequence, ACC recurrence deeply impacts on OS as well as on patients’ quality of life [5].
To date, therapeutic options for ACC are still limited [5]. The lack of significant improvements in medical treatment comparing to the majority of solid tumors is not surprising, given the rarity of the disease and the paucity of the avail- able resources to improve therapeutic strategies [5].
The only chance for cure in patients without metastatic disease is complete primary tumor resection, avoiding effraction of the tumor capsule or spillage of neoplastic cells and achieving microscopically margin-free resection (R0) [9, 10]. Indeed, an incomplete surgical treatment in terms of resection status impairs the definitive survival, as R1 and R2 (defined as microscopic and macroscopic residual disease on margins, respectively) are associated with an increased risk of death compared to R0 margins [5].
Oncological radical resection of adrenal tumor must include en bloc surgical removal of periadrenal fat or even further organs or anatomic structures in case of evidence of infiltration [11]. Lymph node dissection (LND) is sug- gested by the ESES/ENSAT recommendations with both therapeutic and better staging aim [9, 12]. Such recom- mendation relies on the evidence that regional lymph node involvement in ACC has a negative impact on OS and is frequently the cause of locoregional recurrence [9, 13-15]. Indeed, in absence of an accurate LND, nodal status cannot be appropriately evaluated and S-III ACCs could potentially be undertreated [12]. At the same time, metastatic lymph node involvement is associated with incomplete resection status due to the missed dissection of the tumor lymphatic drainage, leading to inferior outcomes [12].
The present study aims to evaluate the oncological benefit of R0 resections for locally advanced disease by comparing the clinical outcomes of S-I and S-II patients, who under- went adrenalectomy, with S-III patients, who underwent extended en bloc surgical resections.
Material and methods
Study design
This is a retrospective cohort study considering patients who underwent adrenalectomy and received pathologic diagnosis of ACC between January 1997 and October 2024 in our national referral center for endocrine surgery.
Data have been prospectively collected in a specifically designed de-identified electronic database. Patients’ follow- up was conducted until 30th November 2024.
All surgical operations of suspicious adrenal lesions and ACC recurrences have been performed by an experienced endocrine surgeon [16, 17].
Inclusion criteria consisted in adult (≥ 18 years-old) patients who underwent index R0 operation in our center for adrenal lesions with diagnosis of ACC after pathologic examination.
Exclusion criteria were: S-IV disease, operations for dis- ease recurrence in patients who underwent index surgery in other centers, S-III patients who did not undergo multivis- ceral en bloc surgical resections in association to adrenal- ectomy plus LND and postoperative follow-up <6 months.
Preoperative data included demographic characteristics (age, BMI, sex as assigned at birth), hormonal hyperfunc- tion, lesion side and size. Operative parameters included intention to treatment surgical technique (open and min- imally-invasive surgery), intention to treatment surgical approach to and per protocol adrenalectomy, including open adrenalectomy, converted adrenalectomy, laparoscopic lat- eral transperitoneal adrenalectomy (LTA), posterior retro- peritoneoscopic adrenalectomy (PRA) and robot-assisted adrenalectomy (RAA) by lateral transperitoneal approach. Conversion rate, LND, extended en bloc surgical resections associated to adrenalectomy and operative time were also considered. Postoperative variables included postoperative intensive unit care stay, early (within 30 days) and late post- operative complications, lesion’s pathologic features (size, histotype, resection status and Ki-67 index-when avail- able), adjuvant therapy (including mitotane, chemotherapy and radiotherapy), locoregional and distant recurrence of the disease, date of the last follow-up or death.
Adjuvant therapy, including mitotane and/or cytotoxic agents (EDP scheme-etoposide, doxorubicin and cisplatin), was administrated in selected cases after accurate multidis- ciplinary evaluation of lesions and patients features. Patients
were addressed to adjuvant radiotherapy in case of risk fac- tors for recurrence, such as high lesion’s dimension, grading (Ki-67 index) and pT4 disease.
Patients were divided into two groups: S-I/II patients and S-III patients.
The primary outcome consisted in the comparison of oncologic outcomes in terms of locoregional recurrence of the disease between S-I/II patients, who underwent adrenal- ectomy, with S-III patients, who underwent extended en bloc surgical resections.
The secondary outcomes of the study were the evaluation of DFS, OS and early postoperative complications rate. A subgroup analysis was also performed to evaluate locore- gional recurrence-related factors.
The study was approved by the Ethical Committee of our Center (ID 5171).
Definitions and surgical planning
Assessment of preoperative work-up was based on guide- lines provided by the National Institutes of Health and rec- ommendations from the ENSAT/ESES societies concerning the care of ACC patients [18-20].
The aim of the surgical treatment was achieving R0 resec- tion status at pathologic examination.
Surgical plan was designed as adrenalectomy alone vs multiorgan resection (adrenal plus at least one or more adja- cent organs and/or venous thrombectomy) basing on pre- and/or intraoperative evidence or suspect of extra-adrenal disease extension. Resection status was defined as R0, R1 or R2 after pathologic examination [18]. LND was performed in both groups basing on pre- and intraoperative suspect of lymph node involvement and/or according to different sug- gestions through the years [9]. LND included as a minimum the periadrenal and renal hilum nodes [9]. In selected cases further nodal dissection included celiac trunk, para-aortic, interaortocaval, retropancreatic, retrocaval, diaphragmatic, right and common hepatic and hepatic hilum nodes.
Surgical procedures included open adrenalectomy, LTA, PRA and RAA, as previously described in details [21].
Operative time is defined as the interval from incision to wound closure (skin to skin). In case of robotic surgeries, operative time also included docking time.
The severity of postoperative complications was graded according to the Clavien-Dindo classification [22].
Disease recurrence was diagnosed based on clinical, labo- ratory results and/or radiological evaluation. Locoregional recurrence has been defined as recurrence of the disease at the surgical site (adrenal lodge or locoregional lymph nodes) [9, 23], while recurrence in other anatomical regions has been defined as progression of systemic disease.
The period of DFS was calculated from the date of the surgical procedure to the last follow-up evaluation of
patients without recurrence. The period of OS for the study was calculated from the date of the surgical procedure to the date of death or of the last follow-up for surviving patients.
Statistical analysis
Baseline characteristics and perioperative variables were compared using a bivariable analysis. Normal distribution was assessed using the Shapiro-Wilks test. Chi-square test was used to compare categorical variables. Continuous vari- ables were expressed as median (interquartile range, IQR). We used paired sample t test or Wilcoxon test to compare continuous variables, depending on data distribution of the analyzed population. Backward stepwise logistic regres- sion (multivariable analysis) was performed to evaluate the potential risk factors for locoregional recurrence. At each step, the variable that had the lowest correlation with the outcome was removed with an elimination criterion set at p> 0.100 and a threshold of p= 0.1 to set a limit on the total number of variables included in the final model. Only variables with a p <0.2 on univariable analysis were entered in the model.
DFS and OS curves were calculated according to the Kaplan-Meier method and were compared by means of the log-rank test.
Statistical analysis was conducted with SPSS 22.0 soft- ware for Windows (SPSS Inc, Chicago, III). MedCalc 18.2.1 (MedCalc Software Ltd, Ostend, BE) was used for survival analysis. All analyses were two tailed, and the threshold for statistical significance was set at p < 0.05.
Results
Among 1098 adrenalectomies performed between January 1997 and October 2024, we selected 65 patients with patho- logic diagnosis of ACC.
Three patients were excluded because they only under- went surgical resection of disease recurrence in our center, while index operation of ACC was performed in other hospi- tals. Eleven patients were excluded due to ENSAT S-IV (oli- gometastatic disease) at time of diagnosis. In these patients, surgical resection of ACC was scheduled to improve clinical management of hypercortisolism-related symptoms. Three further patients were excluded as adrenalectomy was not associated to extended multivisceral en bloc surgical resec- tions, with definitive pathology reporting incidental diag- nosis of S-III disease. Overall, 48 patients met the inclusion criteria: 42 S-I/II patients (including 6 S-I patients and 36 S-II patients) and 6 S-III patients.
In Table 1, details concerning disease staging of S-III patients are provided in extenso.
| TNM | Lymph node dissection | Surgical resections associated to adrenal- ectomy |
|---|---|---|
| pT3 N0 | Renal hilum | Total nephrectomy |
| pT3 N0 | Renal hilum | Total nephrectomy |
| pT3 N0 | Renal hilum | Total nephrectomy |
| pT3 N1 | Renal hilum | Renal vein thrombec- |
| (venous thrombus) | Celiac Trunk | tomy |
| pT2 N1 | Renal hilum | Total nephrectomy |
| Celiac trunk | Splenopancreasectomy | |
| Para-aortic | Left hemicolectomy | |
| Retropancreatic | Omentectomy | |
| Aorto-caval | ||
| pT4 N0 | Renal hilum | Liver S6-S7-S8 resec- tion |
| Aorto-caval Common hepatic artery | ||
| Right hepatic artery Diaphragmatic |
In Table 2, we compared the main perioperative variables of the included patients.
Preoperative features, including demographic characteris- tics, hyperfunction and lesion side were comparable among the two groups.
Open adrenalectomy was scheduled in all S-III patients. Minimally-invasive approach was scheduled in 21 (50%) S-I/ II patients. Conversion to open adrenalectomy was registered in 5 out these 21 patients, justified by tight adhesion due to previous abdominal surgeries (one case) and intraoperative suspect of extra-adrenal extension of the disease (four cases). A detailed description of surgical extent of S-III patients is also reported in Table 1. Multivisceral resections were also performed in 5 S-II patients, consisting in three partial nephrectomies, one total nephrectomy and one splenectomy, due to the intraoperative suspect of focal extension of the disease, with the aim of guarantying R0 resection margins.
Overall, a significant higher rate of S-III patients under- went multivisceral en bloc resections comparing to S-I/II patients: 100% vs 11.9%, respectively (p<0.001).
LND was also performed significantly more often in S-III group (100% S-III patients vs 28.6% S-II patients, p= 0.001).
Median operative time was significantly shorter in S-I/II group (105 vs 236 min, p= 0.008).
The two groups were comparable in terms of postopera- tive intensive care stay, hospital stay and postoperative com- plications. In details, postoperative complications were reg- istered in 10 out of 48 patients of the series: 9 (21.4%) S-I/II patients vs 1 (16.7%) S-III patients (p=0.788). Minor com- plications (≤ II grade according to Clavien-Dindo classifica- tion [22]) occurred in both groups of patients, consisting in
pneumonia (3 S-I/II patients and one S-III patient), wound infection (2 S-I/II patients), urinary infection (2 S-I/II patients) and intra-abdominal collection (1 S-I/II patient). Only one S-I/II patient experienced a major complication for intra-abdominal bleeding, which required reoperation (Clavien-Dindo grade IV[22]).
All surgical resections were confirmed R0 after definitive pathologic evaluation.
Median lesion size was higher in S-III group, though not statistically so (110 vs 92 mm, p= 0.340). Histotype was also evaluated for both groups, with no significative dif- ferences in terms of classical and oncocyte variants. Delv- ing deeper, classical histotype was found in 69% of S-I/II patients and in 66.7% of S-III patients, while oncocyte vari- ant in 13% of S-I/II patients and in 33.3% of S-III patients (p=0.096).
No significant differences were found between the two groups in terms of adjuvant treatments (including mitotane, chemotherapy and radiotherapy).
Comparable locoregional recurrences were reported in the two groups: 8 out of 42 SI-II patients (19%) vs 2 out of 6 S-III patients (33.3%) (p= 0.420). A slight difference in terms of distant recurrences was registered, though not statistically significant: 12 out of 42 SI-II patients (28.6%) vs 4 out of 6 S-III patients (66.7%) (p= 0.064).
Moreover, 2 patients in each group presented both locore- gional and distant recurrence of the disease.
Despite no statistically difference was recognized, we registered median shorter follow-up for S-III patients: 19 (13.2-137.5) months in S-III group vs 44 (19.2-96) months in S-I/II group (p=0.691).
Kaplan-Meier DFS and OS curves were similar among the two groups by means of log-rank test (p= 0.255, p= 0.459, respectively) (Fig. 1, Fig. 2). Delving deeper, 5-years- DFS and 5-years-OS were 49.6% vs 47.9% and 69.2% vs 69.6% in S-I/II group and S-III group, respectively.
After univariable analysis, hyperfunctioning lesions and adjuvant administration of cytotoxic treatments were signifi- cantly associated with locoregional recurrence of the disease (p=0.02, p= 0.04, respectively) (Table 3).
No independent risk factors for locoregional recurrence of the disease were identified after multivariable analysis.
Discussion
This study supports the surgical oncological effectiveness of extended resections of locally advanced ACCs, reporting similar results in terms of locoregional recurrence compared to patients with disease confined to the adrenal gland.
ACC has to be tackled with a limited arsenal of thera- peutic options of which surgery remains the first choice [5]. En bloc complete resection of ACC with the peritumoral/
| Stage I/II | Stage III | p-value | |
|---|---|---|---|
| Patients | 42 | 6 | – |
| Age (years) | 50.5 (39-65) | 48.5 (45.7-64.2) | 0.869 |
| BMI (Kg/m2) | 24.1 (22.4-27.8) | 24.4 (20.5-24.4) | 0.91 |
| Sex | |||
| Male | 17 (40.5%) | 1 (16.7%) | 0.26 |
| Female | 25 (59.5%) | 5 (83.3%) | |
| Hyperfunction | |||
| No | 29 (69.0%) | 3 (50.0%) | 0.355 |
| Yes | 13 (31.0%) | 3 (50.0%) | |
| Side | |||
| Right | 19 (45.2%) | 2 (33.3%) | 0.582 |
| Left | 23 (54.8%) | 4 (66.7%) | |
| Technique | |||
| Open | 21 (50.0%) | 6 (100%) | 0.021 |
| Minimally-invasive | 21 (50.0%) | 0 (%) | |
| Approach | |||
| Open | 21 (50.0%) | 6 (100%) | 0.149 |
| TLA | 13 (31.0%) | 0 (0%) | |
| PRA | 1 (2.4%) | 0 (0%) | |
| RA | 7 (16.6%) | 0 (0%) | |
| Adrenalectomy | |||
| Open | 21 (50.0%) | 6 (100.0%) | 0.255 |
| Conversion | 5 (12.0%) | 0 (0%) | |
| TLA | 10 (23.9%) | 0 (0%) | |
| PRA | 1 (2.3%) | 0 (0%) | |
| RAA | 5 (11.9%) | 0 (0%) | |
| Lymph node dissection | |||
| No | 30 (71.4%) | 0 (0%) | 0.001 |
| Yes | 12 (28.6%) | 6 (100%) | |
| Extended resection | |||
| No | 37 (88.1%) | 0 (0%) | < 0.001 |
| Yes | 5 (11.9%) | 6 (100%) | |
| Operative time (minutes) | 105 (84.2-154.7) | 236 (135.5-336.5) | 0.008 |
| Postoperative Intensive Care | |||
| No | 41 (97.6%) | 5 (83.3%) | 0.101 |
| Yes | 1 (2.4%) | 1 (16.7%) | |
| Postoperative complications | |||
| No | 33 (78.6%) | 5 (83.3%) | 0.788 |
| Yes | 9 (21.4%) | 1 (16.7%) | |
| Tumor size (mm) | 92 (60-128.5) | 110 (71.2-185) | 0.34 |
| Postoperative hospital stay (days) | 5 (3.5-8) | 9 (4-10.5) | 0.449 |
| Histotype | |||
| Classic variant | 29 (69.0%) | 4 (66.7%) | 0.096 |
| Oncocytic variant | 13 (31.0%) | 2 (33.3%) | |
| Adjuvant therapy | |||
| No | 12 (28.6%) | 0 (0%) | 0.131 |
| Yes | 30 (71.4%) | 6 (100%) | |
| Mitotane | |||
| No | 13 (31.0%) | 1 (16.7%) | 0.471 |
| Yes | 29 (69.0%) | 5 (83.3%) |
| Stage I/II | Stage III | p-value | |
|---|---|---|---|
| Chemotherapy | |||
| No | 34 (81.0%) | 4 (66.7%) | 0.42 |
| Yes | 8 (19.0%) | 2 (33.3%) | |
| Radiotherapy | |||
| No | 39 (92.9%) | 5 (83.3%) | 0.43 |
| Yes | 3 (7.1%) | 1 (16.7%) | |
| Locoregional recurrence | |||
| No | 34 (81%) | 4 (66.7%) | 0.42 |
| Yes | 8 (19%) | 2 (33.3%) | |
| Distant recurrence | |||
| No | 30 (71.4%) | 2 (33.3%) | 0.064 |
| Yes | 12 (28.6%) | 4 (66.7%) | |
| Follow-up time (months) | 44 (19.2-96) | 19 (13.2-137.5) | 0.691 |
Continuous variables are expressed as median (IQR)
DFS
100
80
Survival probability (%)
60
Stage
I/II
40
III
20
0
0
20
40
60
80
100
120
140
160
Months
periadrenal fat in absence of capsular effraction is consid- ered the most important component of treatment with cura- tive intent, as is the only chance for long-term cure [2, 5, 9]. Indeed, incomplete surgical radicality relates to increased risk of cancer-related death [5].
Application of neoadjuvant treatment to locally advanced ACC to achieve downsizing/downstaging to potentially allow R0 resection is still not standardized [5, 24, 25]. Sim- ilarly, efficacy of chemotherapy in the adjuvant setting is still debated, mainly due to ACC poor response to cytotoxic treatment [26, 27]. To date, ESES/ENSAT 2018 recommen- dations [9] did not reach consensus on this concern, though panelists suggest that they may be considered in selected patients with very high risk for recurrence. To date, mitotane still remains the only medication specifically approved for
OS
100
80
Survival probability (%)
60
Stage
I/II
40
III
20
0
0
50
100
150
200
250
Months
ACC. Adjuvant early administration of mitotane has been related to improved DFS and OS in advanced disease [3, 11] and it is currently mainly proposed basing on risk factors for disease recurrence, such as Ki-67 ≥ 10%, Rx/R1 resection status and high stage (S-III/IV), balancing them with toxic side effects [4, 11]. Clinical trials such as FIRM-ACT [27] highlighted the efficacy of combination of EDP with mito- tane, with a high rate of objective tumor response and a sig- nificant increased progression-free survival when compared to combination of streptozocin plus mitotane. However, this trial patients’ cohort only included those ones with diagno- sis of ACC not amenable to radical surgical resection [27]. Moreover, ACC has been historically considered a radiore- sistant disease. Retrospective studies on adjuvant use of radi- otherapy in ACC have shown no beneficial effects [26, 28].
| Locoregional recurrence NO | Locoregional recurrence YES | p-value | |
|---|---|---|---|
| n=38 | n=10 | ||
| Stage | |||
| I/II | 34 (89.5%) | 8 (80.0%) | 0.788 |
| III | 4 (10.5%) | 2 (20.0%) | |
| Age (years) | 51 (39-64.2) | 58.5 (41.2-78.7) | 1 |
| Sex | |||
| Male | 16 (42.1%) | 2 (20.0%) | 0.199 |
| Female | 22 (57.9%) | 8 (80.0%) | |
| BMI (Kg/m2) | 25.3 (22.3-29.3) | 23.6 (21.5-24.3) | 0.315 |
| Hyperfunction | |||
| No | 29 (76.3%) | 3 (30.0%) | 0.006 |
| Yes | 9 (23.7%) | 7 (70.0%) | |
| Side | |||
| Right | 16 (42.1%) | 6 (60.0%) | 0.654 |
| Left | 22 (57.9%) | 4 (40.0%) | |
| Approach | |||
| Open | 22 (57.9%) | 5 (50.0%) | 0.537 |
| Conversion | 3 (7.9%) | 2 (20.0%) | |
| Minimally-invasive | 13 (34.2%) | 3 (30.0%) | |
| Lymph node dissection | |||
| No | 23 (60.5%) | 7 (70.0%) | 0.582 |
| Yes | 15 (39.5%) | 3 (30.0%) | |
| Operative time (minutes) | 117.5 (84.2-145) | 179.5 (78.7-252.5) | 0.505 |
| Postoperative complications | |||
| No | 31 (81.6%) | 7 (70.0%) | 0.422 |
| Yes | 7 (18.4%) | 3 (30.0%) | |
| Tumor size (mm) | 92 (47.2-130) | 123.5 (90-159.2) | 0.673 |
| Histotype | |||
| Classic variant | 25 (65.8%) | 8 (80.0%) | 0.388 |
| Oncocytic variant | 13 (34.2%) | 2 (20.0%) | |
| Mitotane | |||
| No | 10 (26.3%) | 4 (40.0%) | 0.397 |
| Yes | 28 (73.7%) | 6 (60.0%) | |
| Chemotherapy | |||
| No | 33 (86.8%) | 5 (50.0%) | 0.011 |
| Yes | 5 (13.2%) | 5 (50.0%) | |
| Radiotherapy | |||
| No | 34 (89.5%) | 10 (100.0%) | 0.284 |
| Yes | 4 (10.5%) | 0 (0.0%) |
Continuous variables are expressed as median (IQR)
As a consequence of the aforementioned considerations, management of locally advanced ACC patients is known to be challenging. Indeed, literature reports suggest that R+ surgery and ENSAT S-III disease represent risk factors for disease recurrence compared to oncological radicality of surgical resection and early ACC stage [5]. Obviously, S-III patients undergoing less than extended surgical
resections theoretically present a higher risk of R+ sur- gery and/or infiltrated margins at pathologic examination.
With regard to the primary endpoint of our study, our results show comparable locoregional recurrence rates between the two groups, with 8 S-I/II and 2 S-III patients developing locoregional disease recurrence (p =0.420).
However, even though R0 resection has been widely defined as the only effective therapeutic strategy [5, 29], literature data on recurrence rate in locally advanced dis- ease are still lacking. A recent ESES panel [29] expressed against nephrectomy in association to adrenalectomy to achieve oncological favorable results, in absence of pre- and intraoperative evidence of extra-adrenal extension of the disease. On the other hand, they reported encouraging outcomes after extended resections due to ACC infiltra- tion of IVC, although such surgical strategies should be demanded in high-expertise hands and in referral centers with multidisciplinary management of the disease [30].
In this context, in our experience, achieving R0 resec- tion margins and avoiding capsular effraction were deemed to be essential to considerably affect the natural history of the disease. Indeed, intraoperative suspect of extra-adrenal extension guided surgical planning even in case of lack of preoperative evidence of infiltration, as definitive patho- logic examination represents the only means to confirm disease stage.
Moreover, to date, there is no clear consensus about the extension of LND in ACC [31]. As a consequence, as long as there is no surgical standard, its exact diagnostic value as well as the oncological effect cannot be still clearly assessed [31]. Discrepant reports regarding lymph node involvement ranging from 4 to 73% [2, 7, 32] suggest that formal regional lymphadenectomy is neither properly per- formed by surgeons nor accurately assessed or reported by pathologists [9]. Furthermore, retrospective data suggest that regional lymph node involvement in ACC negatively impact on OS and is frequently the cause of locoregional recurrence [6, 12, 14]. Concordantly with such literature evidence, we reported a slightly higher rate of locoregional recurrence in patients who did not undergo LND in asso- ciation to the index operation, though not statistically sig- nificative (as reported in Table 3).
The lack of standardization of lymphadenectomy in ACC may also explain the difference of OS and DFS between S-II and S-III patients, as it can be related to understaging thus to undertreatment of S-III patients in adjuvant setting [12].
Nonetheless, our results concerning 5-years-OS and DFS are similar with literature reports [33, 34], being even supe- rior compared to data reported from other authors’ expe- rience [35], thus underlining R0 resection as the critical prognostic factor.
It may be argued that OS and DSF in S-I/II patients could have been affected by the high rate of minimally-invasive surgeries. However, we reported an equal distribution of locoregional recurrences between open (five cases), con- verted (two cases) and minimally invasive (three cases) adrenalectomies. Thus, surgical approach did not represent a risk factor for disease locoregional recurrence.
Indeed, although, in the beginning of laparoscopic application to ACC surgery, minimally invasive approach was associated with a higher frequency of R+ surgery and intra-abdominal recurrences, more recently several meta- analyses did not report impaired oncological outcomes after endoscopic treatment [5, 31, 36-38]. Hence, the choice of the best surgical approach for ACC or suspected malignant adrenal mass should be tailored on preoperative lesion’s fea- tures and evidence of local invasion to achieve a complete resection of the tumoral mass en bloc with the periadre- nal fat to avoid tumor or capsular rupture or spillage [2, 5, 9]. Indeed, even if guidelines from two European societies [9, 39] suggest that potentially malignant adrenal tumors <6 cm without invasion of adjacent organs may be eligi- ble to minimally invasive adrenalectomy, several authors stated that endoscopic approach may not be excluded even in case of preoperative suspect of S-III disease, when sur- gery is performed in experienced hands and in high-volume centers [40, 41]. Interestingly, more recently Olivero et al. [40] reported clinical outcomes of patients with ACC with venous thrombus extension treated with both open and mini- mally invasive approaches, without significative differences among the two groups.
Moreover, the most recent ESES expert opinion [9] described robotic platforms as potential surgical alternative to other minimally invasive approaches even for the treat- ment >6 cm lesions, due to their superiority in terms of three-dimensional vision, dexterity and stability, thus mini- mizing the risk of capsular rupture or R+ margins [39, 41], suggesting that RAA may be the preferred technique if a minimally invasive procedure is pursued [41].
Postoperative complications represent one of the main concerns related to extended surgical resections. Our analy- sis shows comparable results between the two groups (21.4% of S-I/II patients vs 16.7% of S-III patients, p= 0.788), in line with literature data resulting from meta-analysis, rang- ing from median values of 19.4% to 21.4% [38].
Lastly, we made the effort to try to identify potential risk factors for disease locoregional recurrence, though with the limitation of the relatively small sample size dimension. After univariable analysis, hyperfunctioning lesions were related to locoregional recurrence (p =0.006; Odds Ratio 11.7 - Interval of Confidence 95%: 2-66.4), in line with literature reports on their association with increased biological aggressiveness [4]. Administration of adjuvant cytotoxic treatments also significantly related to disease locoregional recurrence (p= 0.011; Odds Ratio 8.5 - Interval of Confidence 95%: 1.7-42.8). Such evidence is not surprising, though apparently paradoxical, as it should be explained by the correct identification of preoperative suspicious lesion’s features of those patients who could have benefit adjuvant treatment the most, despite its afore- mentioned limited efficacy. In this view, adjuvant therapy
should be considered as a predictor factor rather than a risk factor for locoregional disease recurrence. These considerations may also explain the higher rate of distant disease recurrence in S-III patients’ group, as a results of increased biological aggressiveness and unresponsiveness to systemic treatments.
The main limitations of the study are due its monocentric and retrospective nature over a long period involving a rela- tive limited number of patients. However, this aspect should be correlated to the rarity of the disease. On the other hand, the strength of our results relies on the high-volume experi- ence of our referral center, with a case volume of 90 adre- nalectomies per year, and the multidisciplinary management of the disease. The role of the high volume of the center has been underlined by different societies consensus and recom- mendations [9, 16, 19, 29]. In this context, more than ten years ago, we reported one of the preliminary experiences in literature concerning the correlation between center’s volume and oncological outcomes [18]. These results have also been reported in larger retrospective series from MD Anderson Cancer Centre and in a Dutch series, with longer OS for S-I/III patients [31, 32, 42, 43].
Moreover, as far as we know, our reported experience represents the first study which compares oncological outcomes of S-III patients, treated with extended surgical resections, with S-I/II patients.
In conclusion, despite the limitations of the lacking effectiveness of systemic treatment in the adjuvant set- ting, R0 surgical resection seems to relate to improved oncological outcomes of locally advanced ACC.
However, further studies with larger sample size are still necessary to draw definitive conclusions.
Acknowledgements Ministero della Salute - Ricerca Corrente 2025
Authors’ contributions Study conception and design: Priscilla Franc- esca Procopio, Francesco Pennestrì, Marco Raffaelli. Acquisition of data: Antonio Laurino, Priscilla Francesca Procopio, Francesco Pen- nestrì: Analysis and interpretation of data: Francesco Pennestrì, Esther Diana Rossi, Giovanni Schinzari, Alfredo Pontecorvi; Carmela De Crea: Drafting of manuscript: Priscilla Francesca Procopio, Francesco Pennestrì: Critical revision of manuscript: Priscilla Francesca Procopio, Francesco Pennestrì, Antonio Laurino, Esther Diana Rossi, Giovanni Schinzari, Alfredo Pontecorvi, Carmela De Crea, Marco Raffaelli.
Funding Open access funding provided by Università Cattolica del Sacro Cuore within the CRUI-CARE Agreement.
Data availability The raw data supporing the conclusion of this article will be made available by the corresponding author, without undue reservation.
Declarations
Conflict of interest Marco Raffaelli has a consultant agreement with Medtronic, AB Medica, and Intuitive Surgical. Priscilla Francesca Procopio, Francesco Pennestrì and Antonio Laurino have a consult- ant agreement with Medtronic. Carmela De Crea, Esther Diana Rossi,
Giovanni Schinzari and Alfredo Pontecorvi declare that they have no conflicts of interest.
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the insti- tutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Research involving human participants and/or animals This article does not contain any studies with animals performed by any of the authors.
Informed consent Informed consent was obtained from all individual participants for whom identifying information is included in this arti- cle.
Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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