ENDOCRINE SOCIETY
OXFORD
New Findings on Presentation and Outcome of Patients With Adrenocortical Cancer: Results From a National Cohort Study
Soraya Puglisi,10 Anna Calabrese,1 Francesco Ferrau,2 Maria Antonia Violi,2 Marta Laganà,3 Salvatore Grisanti,3 Filippo Ceccato,4 Carla Scaroni,4 Guido Di Dalmazi,5,6 Antonio Stigliano,7 Barbara Altieri,8 Letizia Canu,9 Paola Loli,1º Rosario Pivonello,11 Emanuela Arvat, 12
Valentina Morelli, 13 Paola Perotti,1 Vittoria Basile,1 Paola Berchialla, 14 Sara Urru, 15 Cristian Fiori, 16 Francesco Porpiglia, 16 Alfredo Berruti,3 Anna Pia,1 Giuseppe Reimondo,1 Salvatore Cannavò,2 and Massimo Terzolo1
1Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Hospital, University of Turin, 10043 Turin, Italy
2Endocrine Unit of University Hospital of Messina, University of Messina, 98124 Messina, Italy
3Oncology Unit, University of Brescia, 25123 Brescia, Italy
4Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, 35128 Padua, Italy
5Division of Endocrinology and Diabetes Prevention and Care Unit, IRCCS, University Hospital of Bologna, 40138 Bologna, Italy 6Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy
7Endocrinology, Department of Clinical and Molecular Medicine, Sant’Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy
8Division of Endocrinology and Metabolic Diseases, University-Hospital Gemelli, IRCCS, Catholic University of the Sacred Heart, 00168 Rome, Italy
9Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
10Endocrinology, Clinica Polispecialistica San Carlo, 20037 Milan, Italy
11Endocrinology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
12Oncological Endocrinology Unit, Department of Medical Sciences, University of Turin, 10043 Turin, Italy
13Department of Endocrine and Metabolic Disease, Istituto Auxologico Italiano, IRCCS, 20145 Milan, Italy
14Statistical Unit, Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy
15Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35121 Padua, Italy
16Urology, Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, 10043 Turin, Italy
Correspondence: Soraya Puglisi, MD, PHD, Internal Medicine 1, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano, Italy. Email: soraya.puglisi@unito.it.
Abstract
Context: Because of the rarity of adrenocortical cancer (ACC), only a few population-based studies are available, and they reported limited details in the characterization of patients and their treatment.
Objective: To describe in a nationwide cohort the presentation of patients with ACC, treatment strategies, and potential prognostic factors. Methods: Retrospective analysis of 512 patients with ACC, diagnosed in 12 referral centers in Italy from January 1990 to June 2018.
Results: ACC diagnosed as incidentalomas accounted for overall 38.1% of cases, with a frequency that increases with age and with less aggressive pathological features than symptomatic tumors. Women (60.2%) were younger than men and had smaller tumors, which more frequently secreted hormones. Surgery was mainly done with an open approach (72%), and after surgical resection, 62.7% of patients started adjuvant mitotane therapy. Recurrence after tumor resection occurred in 56.2% of patients. In patients with localized disease, cortisol secretion, ENSAT stage III, Ki67%, and Weiss score were associated with an increased risk of recurrence, whereas margin-free resection, open surgery, and adjuvant mitotane treatment were associated with reduced risk. Death occurred in 38.1% of patients and recurrence-free survival (RFS) predicted overall survival (OS). In localized disease, age, cortisol secretion, Ki67%, ENSAT stage III, and recurrence were associated with increased risk of mortality. ACCs presenting as adrenal incidentalomas showed prolonged RFS and OS.
Conclusion: Our study shows that ACC is a sex-related disease and demonstrates that an incidental presentation is associated with a better outcome. Given the correlation between RFS and OS, RFS may be used as a surrogate endpoint in clinical studies.
Key Words: adrenal incidentaloma, gender disease, mitotane, surgery, recurrence, survival
Abbreviations: ACC, adrenocortical carcinoma; ENSAT, European Network for the Study of Adrenal Tumors; IQR, interquartile range; OS, overall survival; RFS, recurrence-free survival.
Adrenocortical carcinoma (ACC) is an orphan tumor arising from the adrenal cortex that can have an aggressive course (1). Classical estimates of its annual incidence range between 0.7 and 2 cases per million inhabitants (2-5). The rarity of the disease has prevented the acquisition of solid data on its clinical presentation, and it is currently unclear whether either sex- or age-related differences in presentation and outcome ex- ist. Patient sex is not usually regarded as an important prognos- tic factor (6, 7), whereas data on the association of age with outcome are conflicting (6, 8-10). Conversely, there is clear evi- dence that tumor stage, assessed according to the European Network for the Study of Adrenal Tumors (ENSAT) classifica- tion, and grade, assessed by the Ki67 count, are important de- terminants of outcome (11-14). Surgery is the first treatment option and international guidelines recommended to offer high- risk patient adjuvant mitotane treatment (1, 15). In addition to tumor stage, proliferation activity, and complete tumor resec- tion, studies have identified cortisol excess as another predictor of outcome that was associated with worse prognosis (16-18). This is important considering that manifestations of hormonal excess, mainly resulting from hypercortisolism, can be found in up to 60% of patients at diagnosis (19). In the past several dec- ades, an increasing number of ACCs have been discovered ser- endipitously by imaging tests performed for unrelated conditions (20, 21). However, ACCs diagnosed as incidentalo- mas remain poorly characterized in terms of relative prevalence and outcome.
Several population-based studies have been carried out in the United States (2, 4, 6, 22) and, more recently, 1 study was conducted in South Korea (23). Conversely, only 2 population-based studies have been carried out in Europe: a retrospective analysis of 99 patients diagnosed between 1970 and 1984 in Norway (3) and a retrospective study on 359 patients with ACC diagnosed between 1993 and 2010 in the Netherlands (5). In addition, data of 492 patients from the German ACC Registry diagnosed between 1986 and 2007 have been reported in a paper aiming to assess the prognostic value of the staging system for ACC (11).
We present data of a study carried out at tertiary centers for the treatment of adrenal diseases in Italy.
The aims of our study were: (1) to describe how patients with ACC presented at diagnosis in terms of age- and sex- related differences; (2) to assess how patients with ACC were managed; (3) to identify potential predictors of adverse outcome.
Patients and Methods
For this study, we set up a specific web database and invited the tertiary centers for the care of patients with ACC in Italy to participate, providing data on all patients with a patho- logically confirmed diagnosis of ACC who had been pro- actively followed at the centers. Patient data were pseudonymized. Care was taken to prevent duplicate entries of patients who had been followed at different centers. The 12 participating centers, distributed throughout Italy, are listed in Appendix 1 (24).
We retrieved data on patients evaluated from January 1990 to June 2018. Follow-up for this study ended on 31 December
2018. Patients included in the ADIUVO study (www.epiclin. it/adiuvo) were excluded. The study was conducted in accord- ance with the Declaration of Helsinki. The need to obtain in- formed consent from the study participants was waived from the local ethics committees because of the study’s retrospective and observational nature.
The following patient information was retrieved: sex, age, date of diagnosis, hormone secretion, mode of detection (inci- dental, hormone excess, or local symptoms), tumor size and stage, number of metastatic organs (if any), surgical approach, pathology report, adjuvant mitotane, date of recurrence, treatment of advanced disease, date of last follow-up, or death. Biochemical confirmation of hormone excess was re- quested to categorize an ACC as secreting. Tumor stage was established according to the ENSAT classification (stages I and II, confined tumor; stage III, positive lymph nodes or infil- trating neighboring organs/veins without distant metastases; stage IV, distant metastases) (11).
Date of recurrence was defined as the date of appearance of a new lesion confirmed by imaging. Disease recurrence was evaluated using contrast-enhanced computed tomography or magnetic resonance imaging at baseline and every 12 to 18 weeks from the surgery date. Protocols of imaging surveil- lance varied slightly across the centers with an interval be- tween imaging tests ranging from 3 to 6 months.
Statistical Analysis
Categorical data were presented as counts and percentages. Continuous data were presented as medians and interquartile ranges (IQR). Differences in categorical variables were ana- lyzed by the Wilcoxon rank-sum test, whereas differences in continuous variables were analyzed by Pearson’s x2 test. The survival curves were estimated with the Kaplan-Meyer prod- uct limit method. Recurrence-free survival (RFS) was calcu- lated from the time of initial diagnosis to the first radiological evidence of recurrence. Overall survival (OS) was calculated from the initial diagnosis date to the date of death from any cause. Patients who did not experience either recurrence or who did not die were censored at the date of the last follow-up visit for the specific survival analysis. To pre- vent the immortal time bias for patients with early progression or who had died, we calculated RFS and OS estimates from the time point of 3 months, using the landmark method.
Cox proportional hazard regression models were fitted to determine prognostic factors on RFS and OS. The following potential prognostic factors for either RFS or OS were inves- tigated in patients with localized disease (stages I-III): patient age and sex, tumor stage, cortisol secretion, other hormonal secretion, type of presentation, tumor size, Weiss score and Ki67 at diagnosis, surgical approach, resection (R) status, and adjuvant mitotane treatment, whereas recurrence was an- alyzed only for OS. The following potential prognostic factors for OS were investigated in patients with metastatic disease (stage IV) at diagnosis: patient age and sex, tumor size, corti- sol secretion, other hormone secretion, Weiss score, Ki67, and number of metastatic organs at diagnosis.
Correlations and 95% CIs between OS and RFS were meas- ured using normal score rank correlation, calculated using the
| Characteristics | Entire cohort | Women N= 308 | Men N=204 | P value | Incidental N= 181 | Hormone excess N = 208 | Local symptoms N= 86 | P value |
|---|---|---|---|---|---|---|---|---|
| Sex, N (%) | ||||||||
| Valid cases | 512 | 181 | 208 | 86 | <. 01 | |||
| Male | 204 (39.8%) | 82 (45.3%) | 66 (31.7%) | 42 (48.8%) | ||||
| Female | 308 (60.2%) | 99 (54.7%) | 142 (68.3%) | 44 (51.2%) | ||||
| Age, y | ||||||||
| Valid cases | 512 | 308 | 204 | .02 | 181 | 208 | 86 | <. 01 |
| Median (IQR) | 48 (37-59) | 47 (35-58) | 50 (39-59) | 51 (40-61) | 47 (32-58) | 49 (39-60) | ||
| Tumor stage, N (%) | ||||||||
| Valid cases | 481 | 287 | 194 | .86 | 173 | 201 | 84 | .01 |
| Stage I | 40 (8.2%) | 25 (8.7%) | 15 (7.7%) | 20 (11.5%) | 13 (6.5%) | 3 (3.6%) | ||
| Stage II | 247 (51.4%) | 146 (50.9%) | 101 (52.1%) | 97 (56.1%) | 97 (48.3%) | 40 (47.6%) | ||
| Stage III | 93 (19.4%) | 53 (18.4%) | 40 (20.6%) | 33 (19.1%) | 35 (17.4%) | 20 (23.8%) | ||
| Stage IV | 101 (21.0%) | 63 (22.0%) | 38 (19.6%) | 23 (13.3%) | 56 (27.9%) | 21 (25.0%) | ||
| Tumor size, cm | ||||||||
| Valid cases | 470 | 277 | 193 | .03 | 167 | 196 | 83 | <. 01 |
| Median (IQR) | 10 (7-13) | 9.5 (7-12.7) | 10 (7-14) | 9 (6-12) | 10 (7-13) | 12 (9-18) | ||
| Hormone secretion, N (%) | ||||||||
| Valid cases | 480 | 289 | 191 | <. 01 | 175 | 208 | 79 | <. 01 |
| No | 219 (45.6%) | 114 (39.5%) | 105 (55.0%) | 129 (73.7%) | 0 (0%) | 72 (100%) | ||
| Yes | 261 (54.4%) | 175 (60.5%) | 86 (45.0%) | 46 (26.3%) | 208 (100%) | 7 (0.0%) | ||
| Cortisol ± other hormones | 198 (75.9%) | 123 (70.3%) | 75 (87.2%) | 38 (82.6%) | 156 (75.0%) | 4 (57.1%) | ||
| Androgen (in women) | 45 (17.2%) | 45 (25.7%) | 0 (0.0%) | 6 (13.0%) | 37 (17.8%) | 2 (28.6%) | ||
| Estrogen (in men) | 7 (2.7%) | 0 (0.0%) | 7 (8.1%) | 1 (2.2%) | 6 (2.9%) | 0 (0.0%) | ||
| Mineralocorticoid | 11 (4.2%) | 7 (4.0%) | 4 (4.7%) | 1 (2.2%) | 9 (4.3%) | 1 (14.3%) | ||
| Incidentaloma, N (%) | ||||||||
| Valid cases | 475 | 285 | 190 | .06 | ||||
| Yes | 181 (38.1%) | 99 (34.7%) | 82 (43.2%) | |||||
| No | 294 (61.9%) | 186 (65.3%) | 108 (56.8%) | |||||
| Weiss score | ||||||||
| Valid cases | 284 | 167 | 117 | .52 | 108 | 111 | 49 | <. 01 |
| Median (IQR) | 6 (5-7) | 6 (5-7) | 6 (5-8) | 5 (4-7) | 6 (5-8) | 6 (5-8) | ||
| Ki67 | ||||||||
| Valid cases | 310 | 183 | 127 | .25 | 121 | 116 | 58 | <. 01 |
| Median (IQR) | 16 (8-30) | 20 (8-30) | 15 (6-30) | 11 (5-20) | 20 (10-30) | 20 (10-40) |
Bold indicates statistically significant values.
Abbreviation: IQR, interquartile range.
“Mode of detection was known in 475 patients. Patients who were symptomatic for both hormone excess and local symptoms were counted in the category “hormone excess.”
iterative multiple imputation approach for analysis of correla- tions between 2 partially censored failure times (25). Although this approach is semiparametric because it does not require any assumptions about the marginal distributions, it uses a Gaussian dependency structure, which may lead to bias from misspecification. We thus also computed the rank correlation between OS and RFS using a nonparametric esti- mator of Spearman’s correlation, based on a nonparametric bivariate survival surface estimator (26). Bootstrap resam- pling was implemented to compute 95% CIs. Both methods have their own limitations. Although the nonparametric method does not make assumptions about the underlying cor- relation structure and therefore is less prone to bias, the
semiparametric method appears more stable than non- parametric estimators, particularly for small sample sizes. For these reasons, we reported the results of both methods.
All reported P values are 2-sided. P values <. 05 were con- sidered statistically significant. Statistical analyses were per- formed with R, version 4.0 (R Core Team, USA).
Results
Patient Characteristics at Clinical Presentation
A total of 512 patients were included in the study; their char- acteristics at diagnosis are shown in Table 1.
70%
60%
50%
40%
30%
20%
10%
0%
< 10
11-20
21-30
31-40
41-50
51-60
61-70
71-80
>80
Age (years)
Valid cases = 475
The median age was 48 (37-59) years and most patients had stage II ACC (51%), whereas only 21% showed stage IV ACC, mainly with 1 (41.6%) or 2 (30.7%) metastatic organs. Only 1 patient had a familial history of ACC that was associ- ated with TP53 mutation. Median follow-up was 30 (IQR, 10 to 62) months.
Women were younger than men, and their ACCs were smaller and more frequently steroid-secreting (Table 1). In both sexes, the most common steroid secretion was cortisol (alone or in combination with other hormones), followed by androgen secretion in women. ACC presented as an adrenal incidentaloma in 38.1% of cases, ranging from <20% in pa- tients younger than aged 30 years to more than 50% in pa- tients aged older than 70 years (Fig. 1). ACCs presenting as adrenal incidentalomas were smaller, of early stage, less fre- quently secreting, and with less aggressive pathological fea- tures (Table 1).
First-line Treatment
Localized disease (380 patients with stage I-III ACC)
Surgery was the first treatment in all evaluable cases (missing data in 9 patients), with a predominance of open surgery (72%). The surgical approach differed by stage (P <. 01), with more laparoscopic surgery in stage I (62%) and more open surgery in stages II and III (71% and 90%, respectively) (Table 2).
After radical surgical resection, 226 of 360 (62.7%) pa- tients (missing data in 20 cases) received adjuvant therapy with mitotane. Patients who were treated with mitotane pre- sented with larger (P = . 01) and more frequently symptomatic (P <. 04) tumors, together with more aggressive pathological features, such as higher Weiss score (P <. 01) and higher Ki-67 (P <. 01), than patients who underwent surveillance only (Table 2). Moreover, mitotane treatment increased
with stage (P <. 01): 45% of stage I, 62% of stage II, and 73% of stage III patients with ACCs underwent adjuvant mitotane.
Metastatic disease (101 patients with stage IV ACC)
Surgery was performed in 71 patients (70.3%), which was mainly open (45 of 71, 63.3%). Medical treatment was initi- ated in 89 patients (88.1%), in most cases (76.4%) with a combination of mitotane and chemotherapy, whereas mito- tane alone was administered in 13 patients (14.6%) and chemotherapy alone in 8 patients (9%). Age differed between the patients who received different types of treatment (mito- tane and chemotherapy median age, 42.5; IQR 34 to 53.25 years; mitotane alone, 68; IQR 64 to 72 years; chemo- therapy alone, 58, IQR 56 to 68 years; P <. 001). No other significant statistical difference among these groups was found.
Outcomes
Recurrence free survival
The median follow-up for RFS was 15 (IQR, 5 to 41) months. Excluding the 8 patients with macroscopic residual tumor after surgery (R2), recurrence occurred in 209 of 372 patients (56.2%). There was an inverse relationship between the dur- ation of RFS and tumor stage (Fig. 2A). RFS at 5 years was 33% (95% CI, 28-39), with 59% (95% CI, 43-80) for stage I ACC, 36% (95% CI, 29-44) for stage II, and 16% (95% CI, 9-27) for stage III.
The median follow-up for RFS for patients still alive at the study closure was 18 (IQR, 6 to 48.5) months.
ACCs presenting as adrenal incidentalomas showed pro- longed RFS (Fig. 2B).
At multivariate analysis, stage III, cortisol secretion, Weiss score, and Ki67 were associated with an increased risk of
| Characteristics | Open surgery N= 267 | Laparoscopy N= 104 | P value | Mitotane N = 226 | Surveillance only N= 134 | P value |
|---|---|---|---|---|---|---|
| Age, y | ||||||
| Valid cases | 267 | 104 | .12 | 226 | 134 | .65 |
| Median (IQR) | 48 (36.2-58.0) | 49.5 (36.8-59.3) | 48 (36-58) | 49 (37-60) | ||
| Sex, N (%) | ||||||
| Valid cases | 267 | 104 | .53 | 226 | 134 | .95 |
| Male | 116 (43.4%) | 36 (34.6%) | 92 (40.7%) | 55 (41.0%) | ||
| Female | 151 (56.6%) | 68 (65.4%) | 134 (59.3%) | 79 (59.0%) | ||
| Tumor stage, N (%) | ||||||
| Valid cases | 267 | 104 | <. 01 | 226 | 134 | <. 01 |
| Stage I | 15 (5.6%) | 24 (23.1%) | 18 (8.0%) | 22 (16.4%) | ||
| Stage II | 171 (64.1%) | 71 (68.3%) | 145 (64.1%) | 89 (66.4%) | ||
| Stage III | 81 (30.3%) | 9 (8.6%) | 63 (27.9%) | 23 (17.2%) | ||
| Tumor size, cm | ||||||
| Valid cases | 256 | 103 | <. 01 | 220 | 127 | .01 |
| Median (IQR) | 10 (7.8-14) | 6 (5-8) | 10 (7-14) | 8 (6-12) | ||
| Hormone secretion, N (%) | ||||||
| Valid cases | 254 | 100 | .66 | 216 | 127 | .04 |
| Yes | 131 (51.6%) | 49 (49.0%) | 120 (55.6%) | 56 (44.1%) | ||
| No | 123 (48.4%) | 51(51.0%) | 96 (44.4%) | 71 (55.9%) | ||
| Incidentalomas, N (%) | ||||||
| Valid cases | 250 | 100 | .09 | 214 | 126 | .04 |
| Yes | 98 (39.2%) | 49 (49.0%) | 81 (37.9%) | 62 (49.2%) | ||
| No | 152 (60.8%) | 51 (51.0%) | 133 (62.1%) | 64 (50.8%) | ||
| Weiss score | ||||||
| Valid cases | 169 | 76 | .14 | 161 | 82 | <. 01 |
| Median (IQR) | 6 (5-7) | 6 (5-8) | 6 (5-8) | 5 (4-7) | ||
| Ki67 | ||||||
| Valid cases | 184 | 79 | .02 | 172 | 90 | <. 01 |
| Median (IQR) | 18 (8-30) | 12 (5-20) | 20 (10-31) | 10 (5-18) | ||
| ≤10% | 60 (32.6%) | 37 (46.8%) | 47 (27.3%) | 50 (55.6%) | ||
| >10% | 124 (67.4%) | 42 (53.2%) | 125 (72.7%) | 40 (44.4%) | ||
| Resection status, N (%) | ||||||
| Valid cases | 257 | 99 | .07 | 219 | 127 | .70 |
| R0 | 166 (64.6%) | 74 (74.8%) | 153 (69.9%) | 83 (65.3%) | ||
| R1/RX | 86 (33.5%) | 22 (22.2%) | 61 (27.8%) | 42 (33.1%) | ||
| R2 | 5 (1.9) | 3 (3.0%) | 5 (2.3%) | 2 (1.6%) | ||
Bold indicates statistically significant values.
Abbreviation: IQR, interquartile range.
recurrence, whereas margin-free resection (R0), open surgery, and adjuvant mitotane treatment were associated with pro- longed RFS (Table 3; Fig. 3).
Overall survival
The median follow-up for OS was 30 (10-62.25) months. Death occurred in 195 of 512 (38.1%) patients. OS progres- sively decreased with advanced stage (Fig. 4A). OS at 5 years was 54% (95% CI, 49-60), with 71% for stage I ACC (95% CI, 55-92), 68% (95% CI, 61-75) for stage II, 41% (95% CI, 30-56) for stage III, and 13% (95% CI, 6-28) for stage IV.
The median follow-up for OS for patients still alive at the study closure was 34 (IQR, 13.75 to 69.25) months. ACCs
presenting as adrenal incidentalomas tumor showed pro- longed OS (Fig. 4B). In patients with localized disease, multi- variate analysis showed that age at diagnosis, stage III, cortisol secretion, Ki67, and the event of recurrence were associated with increased mortality (Table 3).
The p correlation between OS and RFS was 0.82 (95% CI 0.74 to 0.87), using the iterative multiple imputation ap- proach, and 0.70 (0.59 to 0.78), using a non-parametric esti- mator of Spearman’s correlation (Fig. 5).
At multivariate analysis, in patients with metastatic disease, only cortisol secretion (hazard ratio, 2.05; 95% CI, 1.06-3.98, P <. 05) and number of metastatic organs (hazard ratio, 1.77; 95% CI, 1.26-2.50, P <. 001) were associated with increased mortality (Supplementary Table 1) (27).
A
B
1.00
1.00
Recurrence-free survival probability
ENSAT Stage I
Recurrence-free survival probability
Incidental tumor
ENSAT Stage !!
Hormone excess
0.75
ENSAT Stage III
0.75
Local symptoms
0.50
0.50
0.25
0.25
p < 0.0001
p < 0.0001
0.00
0.00
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time
Time
Number at risk
Number at risk
ENSAT Stage
36
29
23
19
17
13
11
8
6
1
1
1
1
0
0
0
Incidental tumor
133
94
70
57
46
35
29
20
18
11
8
6
5
4
3
2
ENSAT Stage II
226
157
110
86
70
48
38
24
19
17
13
11
10
7
6
4
Hormone excess
139
84
50
34
26
19
15
9
6
6
5
5
5
3
3
3
ENSAT Stage III
84
40
21
16
9
8
6
4
4
3
3
3
3
3
2
2
Local symptoms
54
34
22
19
14
7
4
2
1
1
1
1
1
1
0
0
Discussion
The availability of a large cohort of well-characterized pa- tients with ACC enabled us to retrieve interesting data on clin- ical presentation, prognostication, and outcome of this rare tumor.
A slight predominance of women was found, confirming previous reports (4-6, 9, 22, 23). After further investigations, women were found to be younger than men and harboring smaller tumors that were more frequently steroid-secreting.
Given the increasingly higher number of adrenal incidenta- lomas detected in everyday practice (26, 27), we focused on the incidental presentation of ACC, which in our study was more frequent (38.1%) than reported in a few previous studies (approximately 18%) (9, 23). In our cohort, incidental pres- entation of ACC increased with age, paralleling the age distri- bution of adrenal incidentalomas. However, a notable number of incidental ACCs was found even among younger patients. It is currently not known whether the serendipitous discovery of an adrenal tumor offers the opportunity for an early diagnosis because the issue of ACCs presenting as adrenal incidentalomas has been almost neglected. Importantly, in our study, ACCs presenting as adrenal inci- dentalomas were diagnosed at an early stage, with a smaller size and less aggressive pathological features than symptomat- ic tumors. Patients with incidental ACCs were thus found to have prolonged RFS and OS compared with patients with symptomatic tumors. In multivariable analysis, the effect of incidental presentation was no longer evident because it was linked to favorable parameters (stage, pathological features), which are the main drivers of prognosis. From a clinical view- point, however, the present findings show that the serendipit- ous detection of an ACC provides the opportunity for an early diagnosis, thus underlining the importance of confidently ex- cluding the possibility of ACC in all patients with an adrenal incidentaloma, and to offer prompt surgery to patients with suspicious tumors (28).
Previous population-based studies on patients with ACC have already demonstrated that ENSAT stage and tumor grade at diagnosis are significantly associated with survival (5, 6), which was confirmed by our findings.
We carried out a study of the management of ACC in Italy. Although open surgery was most frequently performed in
patients with localized disease (72%), laparoscopic surgery was preferred in smaller tumors and stage I ACC. This is con- sidered reasonable according to international guidelines (1, 15); however, the role of laparoscopic surgery in the man- agement of ACC remains controversial. In the present study, open surgery was associated with a slightly beneficial effect on the risk of recurrence, despite that this approach was used in patients with worse prognostic factors. This reinforces the idea that open surgery is the treatment standard (29, 30), at least for patients with locally advanced disease (31), to min- imize the risk of peritoneal carcinomatosis (32).
Although it is biologically plausible that disease recurrence portends a worse prognosis, this is the first study to formally demonstrate the significant impact of an ACC recurrence on survival. We also showed a correlation between RFS and OS, thus suggesting that RFS is an adequate surrogate for OS also for patients with ACC, as reported for other tumors (33-35). The demonstration that ACC recurrence is a strong predictor of death underscores the importance of developing adjuvant concepts to prevent disease recurrence. Uncertainty remains regarding the value of adjuvant mitotane despite international guidelines recommending its use after surgery in patients at high risk of recurrence (1, 15). Therefore, the finding that adjuvant mitotane treatment is linked to a re- duced recurrence risk, despite the worst characteristics of treated patients (larger and symptomatic tumors and higher Weiss scores and Ki-67% compared with the group on surveil- lance only), supports mitotane use in an adjuvant setting. Follow-up is likely immature to demonstrate an effect of adju- vant mitotane on OS in nonmetastatic ACC. Interestingly, this is the first time that adjuvant mitotane therapy has been assessed in a population-based study; previous population- based studies did not capture data on adjuvant medical ther- apy (5, 6) or show aggregate data including different adjuvant treatments (mitotane, radiotherapy, and chemotherapy) as a single variable (22, 23). In our study, adjuvant mitotane treat- ment was used extensively probably because a seminal paper on this treatment was published in 2007 by Italian and German centers (36).
In patients with metastatic presentation, multimodal treat- ment was the most common strategy, as international guide- lines recommend (1, 15). Although recent papers seem to demonstrate that cytoreductive surgery of the primary tumor
| Factor | RFS | OS | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Age at diagnosis | 1.01* | 1.00-1.03 | .082 | 1.04* | 1.01-1.07 | .003 |
| Male sex | 0.78 | 0.50-1.23 | .30 | .69 | 0.39-1.24 | .213 |
| ENSAT Tumor stageª | 2.18 | 1.54-3.11 | <. 001 | 2.06 | 1.27-3.36 | .004 |
| Tumor size | 1.04* | 0.99-1.09 | .103 | 1.01* | 0.97-1.06 | .546 |
| Cortisol secretionb | 2.17 | 1.50-3.12 | <. 001 | 2.15 | 1.34-3.46 | .002 |
| Other hormone secretion™ | 1.19 | 0.71-1.97 | .509 | 1.40 | 0.71-2.77 | .330 |
| Incidental presentationd | 0.73 | 0.45-1.20 | .214 | 1.03 | 0.55-1.93 | .927 |
| R statuse | 0.56 | 0.36-0.88 | .013 | 0.92 | 0.48-1.79 | .811 |
| Weiss score | 1.26* | 1.08-1.47 | .003 | 1.05* | 0.88-1.26 | .590 |
| Ki67 | 1.03* | 1.01-1.04 | <. 001 | 1.02* | 1.01-1.04 | .004 |
| Open surgeryf | 0.67 | 0.46-1.00 | .047 | 0.94 | 0.47-1.89 | .865 |
| Adjuvant mitotane therapy® | 0.55 | 0.34-0.88 | .012 | — | — | — |
| History of recurrence | — | — | — | 11.09 | 2.65-46.43 | .001 |
Bold indicates statistically significant values.
Abbreviations: ENSAT, European Network for the Study of Adrenal Tumors; HR, hazard ratio; OS, overall survival; RFS, recurrence-free survival. *Per unit increase.
Reference categories are as follows:
“ENSAT stage III vs I-II.
bCortisol-secreting tumors vs not-secreting tumors; the category “cortisol secretion” includes tumors secreting cortisol with or without other steroids. “Other hormone-secreting tumors vs not-secreting tumors; the category “other steroid secretion” includes secretion of any steroid except cortisol.
ªIncidental tumors vs symptomatic tumors.
RO vs R1-Rx.
fOpen vs laparoscopic surgery.
8Adjuvant mitotane vs surveillance only.
1.00
Recurrence-free survival probability
- Surveillance only
0.75
- Mitotane therapy
0.50
0.25
p = 0.02
0.00
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time
Number at risk
Surveillance only
125
84
54
42
31
18
15
10
9
6
5
5
4
3
2
1
Mitotane therapy
213
137
97
76
63
49
38
26
20
15
12
10
10
7
6
5
in patients with metastasis is associated with prolonged sur- vival (6, 37), we found no evidence of this; however, the num- ber of patients with stage IV at diagnosis was rather limited. We should acknowledge that patients with advanced ACC may be underrepresented in our study because most of the re- ferral centers in Italy are endocrine departments and such pa- tients may be referred to oncological departments. Because of
the long time frame of data capture, which applies to all population-based studies, the technical changes in imaging and surgical techniques represent another limitation, together with the retrospective nature of the analysis.
The strengths of our analysis are the large sample size, the availability of detailed clinical annotation and complete follow-up information, plus the use of similar protocols for
A
B
1.00
1.00
ENSAT Stage |
Incidental tumor
ENSAT Stage Il
Overall survival probability
+ Hormone excess
Overall survival probability
0.75
ENSAT Stage III
ENSAT Stage VI
0.75
Local symptoms
0.50
0.50
0.25
0.25
p < 0.0001
p = 0.00057
0.00
0.00
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time
Time
Number at risk
Number at risk
ENSAT Stage
40
32
30
23
21
14
13
10
9
5
5
2
1
0
0
0
Incidental tumor
181
131
111
88
73
56
44
39
36
27
24
19
17
11
10
9
ENSAT Stage II
247
195
160
125
101
81
63
52
43
37
32
26
24
17
16
15
ENSAT Stage III
93
68
51
38
28
21
16
13
13
10
10
10
8
7
4
4
Hormone excess
208
150
104
76
51
42
32
25
20
19
17
14
11
9
8
7
ENSAT Stage VI
101
46
24
17
8
4
2
2
1
1
1
0
0
0
0
0
Local symptoms
86
55
44
33
28
17
13
9
7
4
4
3
2
2
1
1
A
B
0.0 0.2 0.4 0.6 0.8 1.0
· Uncensored
*
Event
RFS is censored
Censored
400
. OS is censored
Doubly Censored
£(t)
300
OS
200
100
0.0
0.6
0
0.2
0.4
Ê(t2)
0.8
1.0
0
100
200
300
400
RFS
diagnosis, surveillance, and treatment across the different centers.
Conclusions
In a large and well-characterized cohort of patients with ACC, our study shows that ACC is a sex-related disease and demon- strates that both tumor characteristics (tumor stage and size, hormonal secretion, Ki67%, Weiss score) and treatment strat- egies (open surgery, adjuvant mitotane) have an impact on clinical outcome. We demonstrate for the first time that inci- dental ACC may have a better prognosis than symptomatic tu- mors and that disease recurrence is a strong predictor of mortality. These findings highlight the value of surgery and adjuvant mitotane to prevent recurrence and improve patient outcome. Open surgery appears to be the most effective way of removing ACC.
Finally, the present study provides information on the man- agement of patients with ACC in Italy, which could be used as a benchmark for future studies.
Funding
The research was supported by funding for Massimo Terzolo from the Italian Association for Cancer Research
(Associazione Italiana per la Ricerca sul Cancro), grant num- ber IG2019-23069.
Disclosures
M.T. received research grants from HRA Pharma and advis- ory board honoraria from HRA Pharma and Corcept Therapeutics. S.C. received board honoraria from HRA Pharma. The other authors have stated there are no conflicts of interest in connection with this article. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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