ORIGINAL ARTICLE
Prognostic factors in adrenocortical carcinoma: data from a large Polish series
Karolina M. Nowak1, Radosław Samsel2, Andrzej Cichocki2, Urszula Ambroziak3, Katarzyna Roszkowska-Purska4, Agnieszka Łebek-Szatańska1, Łukasz Koperski5, Maciej Otto6, Wojciech Zgliczyński1, Lucyna Papierska1
1 Department of Endocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland
2 Division of Surgery, Department of Oncology, Memorial M. Skłodowska-Curie Cancer Institute, Warsaw, Poland
3 Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland
4 Department of Pathology, Memorial M. Skłodowska-Curie Cancer Institute, Warsaw, Poland
5 Department of Pathology, Medical University of Warsaw, Warsaw, Poland
6 Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland
KEY WORDS
adrenocortical carcinoma, Ki67, mitotane, prognostic factors
ABSTRACT
INTRODUCTION Adrenocortical carcinoma (ACC) is a rare malignancy, associated with poor outcome and few therapeutic options. Despite increasing attention, the knowledge about the clinical course and treatment of these tumors is limited.
OBJECTIVES Survival rates in ACC are still low and the percentage of relapse is high. Thus, it is crucial to identify the prognostic factors of overall survival (OS) and recurrence-free survival (RFS).
PATIENTS AND METHODS This was a retrospective analysis of 66 patients diagnosed with ACC between 2002 and 2015.
RESULTS The median OS was 43.5 months, 78.19 months for stage I + II, 22.95 months for stage III, and 19.54 months for stage IV ACC. Older age, stage IV ACC, margin status R2, and no mitotane treatment were associated with poor OS. Low Ki67 and mitotic indices were related to improved OS in a univariate analysis. The median RFS was 101.1 months. Disease recurrence after potentially curative surgery was reported in 1 patient (25%) with stage I, 12 patients (46%) with stage II, and 9 patients (45%) with stage III ACC. Male sex and no mitotane treatment were associated with a reduced RFS in a multivariate analysis and higher Ki67 and mitotic indices in the univariate analysis.
CONCLUSIONS Ki67 and mitotic indices should be considered as prognostic factors when planning the adjuvant treatment of ACC. Mitotane treatment may be independently associated with better out- comes regardless of the tumor stage.
Correspondence to: Karolina M. Nowak, Klinika Endokrynologii, Centrum Medycznego Kształcenia Podyplomowego, Szpital Bielański, ul. Cegłowska 80, 01-809 Warszawa, Poland, phone: +48 22 569 05 29, email: knowak@cmkp.edu.pl Received: March 3, 2018. Revision accepted: May 4, 2018. Published online: May 4, 2018. Conflict of interest: none declared. Pol Arch Intern Med. 2018; 128 (6): 371-378 doi:10.20452/pamw.4260 Copyright by Medycyna Praktyczna, Kraków 2018
INTRODUCTION Adrenocortical carcinoma (ACC) is a malignant tumor, associated with poor prog- nosis. Although this type of cancer is generally rare (0.5-2 cases/million/year),1 it was the most common finding after surgery (25.2%) in a series of 139 cases of adrenal tumors greater than 5 cm in size.2 The 5-year survival rates in this aggres- sive cancer range between 16% and 44%,3 while the median overall survival (OS) varies from 32 to 77 months.1,4-7 Due to poor long-term outcome in patients with ACC, numerous retrospective studies have been conducted to identify prognostic factors.
Prognosis of ACC is dependent on the tumor stage at presentation. Although the survival rates
in advanced disease are still low, more recent stud- ies suggest that prognosis in early stages is im- proving.3,5 The European Network for the Study of Adrenal Tumors (ENSAT) staging system has a better prognostic stratification than the Inter- national Union Against Cancer classification; thus, it is widely used in contemporary studies.8 Stage I is defined as a tumor size of 5 cm or low- er; stage II, as a tumor size of more than 5 cm; stage III, any tumor size plus one of the follow- ing: tumor infiltration into surrounding organs, such as the kidney, pancreas, spleen, and liver or large blood vessels (renal vein or vena cava); and, finally, stage IV is defined as distant metastases.8
| Parameter | Nonmissing observations | Value | |
|---|---|---|---|
| Age, y, mean (SD) | 66 | 51.4 (14) | |
| Sex, female/male, n | 66 | 43/23 | |
| Hormonal activity, n (%) | 56 | 33 (58.9) | |
| Tumor size, mm, mean (SD) | 63 | 114.25 (50.66) | |
| ENSAT stage, n (%) | I | 4 | 4 (6.1) |
| II | 26 | 26 (39.4) | |
| III | 25 | 25 (37.9) | |
| IV | 11 | 11 (16.7) | |
| Capsular invasion with crossing its border, n (%) | 62 | 26 (41.9) | |
| Capsular invasion without crossing its border, n (%) | 62 | 17 (27.4) | |
| Invasion in capsular vessels, n (%) | 62 | 28 (45.2) | |
| Tumor infiltration into surrounding tissue, n (%) | 62 | 22 (35.5) | |
| Tumor invasion in adjacent organ, n (%) | 62 | 16 (25.8) | |
| Presence of necrosis, n (%) | 50 | 40 (80.0) | |
| Necrosis, %, mean (SD) | 26 | 43 (19.55) | |
| Necrosis ≥50%, n (%) | 26 | 13 (50.0) | |
| Venous tumor thrombus in vena or renal vein, n (%) | 61 | 8 (13.1) | |
| Ki67 index, %, mean (SD) | 56 | 23.55 (21.5) | |
| Ki67 index ≥10%, n (%) | 56 | 38 (67.9) | |
| Mitotic index per 50 HPF, mean (SD) | 38 | 37.25 (40.16) | |
| Mitotic index per 50 HPF ≥20, n (%) | 38 | 19 (50.0) | |
| Mitotane treatment, n (%) | 64 | 57 (89.1) | |
| Duration of mitotane treatment, mo, mean (SD) | 49 | 31.2 (24) | |
| Margin status R0, n (%) | 50 | 50 (76.9) | |
| Margin status R1, n (%) | 3 | 3 (4.6) | |
| Margin status R2, n (%) | 7 | 7 (10.8) | |
| Death, n (%) | 66 | 34 (51.5) | |
| Recurrent disease, n (%) | 41 | 20 (48.8) | |
Abbreviations: ENSAT, European Network for the Study of Adrenal Tumors; R0, uninvolved; HPF, high power field; R1, microscopically involved; R2, macroscopically involved
In a study by Ayala-Ramirez et al6 and Fassnacht et al,8 the 5-year OS rates were 66% and 80%, respectively, for stage I; 58% and 61%, respec- tively, for stage II; 24% and 50%, respectively, for stage III; and 0% and 13%, respectively, for stage IV disease. The median OS was 289.2, 73, 41.6, and 10.7 months for stages I, II, III and IV, respectively.6
The 5-year survival after surgery was reported to be 46%, 21%, and 10% for uninvolved (RO), mi- croscopically involved (R1), and macroscopically involved (R2) margins, respectively.9
The Ki67 proliferation index was found to play a major role in predicting recurrence in patients with stages I to III after complete resection (R0).10 Ki67 was also found to be a prognostic factor of OS in patients with stage IV disease.11
Data on the association between hormonal ac- tivity and poorer prognosis are inconsistent. One of the studies did not identify it as a prognostic factor,12 while other authors reported that pa- tients with cortisol-secreting tumors had shorter
recurrence-free survival (RFS),13 OS,14 or both disease-free survival and OS.15 Another factor as- sociated with poor survival is older age.7,14
The adjuvant mitotane treatment may improve survival in stages I to III of ACC;12 nevertheless, such treatment is not always recommended in ear- ly stages.16 Due to the toxicity of mitotane, discus- sions are ongoing which patients will benefit from this treatment. The clinical practice guidelines of the European Society for Medical Oncology (ESMO) stratify a risk for recurrence as “low risk” in patients with complete resection (R0), stages I and II, and Ki67 of less than 10%.16 Patients are defined as “high-risk” in the case of uninvolved margins (R0) after surgery, together with stage III disease or Ki67 of 10% or higher. Although ac- cording to the ESMO the mitotane treatment is not mandatory in low-risk patients, they can suf- fer from recurrence,17 and even in stages I and II of the disease, the percentage of relapse is high and reaches 27% and 46%, respectively.14
“High-grade ACC”, defined as a mitotic count of at least 20/50 high-power fields (HPF), was associ- ated with poorer prognosis than “low-grade ACC” (<20/50 HPF).18 In another study, together with the mitotic rate of more than 5/50 HPF, several features were reported to be useful in outcome prediction, namely, distant metastasis at initial presentation,5,19 tumor invasion of the vessels, tu- mor capsule, or adjacent organs, and tumor ne- crosis.19 Disease-free survival was different for pa- tients with 1 to 2, 3 to 4, and more than 4 features (84%, 37%, and 9%, respectively). Only the mi- totic rate exceeding 5/50 HPF was found to be a prognostic factor in a multivariate analysis in patients without distant metastasis at diagnosis.19
Since the recurrence of the disease is still very common even after complete resection and in the lower stages of the disease, there is a need to identify prognostic factors that would help identi- fy patients requiring a more aggressive treatment. Therefore, the aim of the study was to identify the prognostic factors of RFS and OS in Polish pa- tients with ACC. The second objective was to ver- ify treatment results in the studied population.
PATIENTS AND METHODS We included a total of 66 adult patients enrolled retrospectively from the Polish Registry of Adrenocortical Carcino- ma. The patients were diagnosed with ACC be- tween 2002 and 2015 in 1 of the 3 participating endocrinology departments in Warsaw, Poland. The baseline characteristics of the patients are presented in TABLE 1. Of the 66 patients, 61 un- derwent an open adrenalectomy in 1 of the 2 sur- gical departments. The margin status was evalu- ated based on surgical and pathological reports. Five patients with stage III disease had an inop- erable tumor due to its local invasion into sur- rounding vital organs. The functional status of ACC was evaluated with standard hormonal tests. Recurrent disease was defined as a new lesion confirmed by imaging tests. The RFS was deter- mined as time from surgery to the date of first
evidence of relapse on imaging tests and was cal- culated only for patients with stages I to III af- ter complete resection (RO) (intention to cure). The follow-up lasted until June 2016. To identify the prognostic factors of OS and RFS, a number of clinical and histological features were investi- gated: age, sex, ENSAT stage,10 hormonal activi- ty, tumor size, margin status, mitotic index, and Ki67 index. The study was approved by the ethics committee of the Centre of Postgraduate Medi- cal Education in Warsaw.
Statistical analysis Percentages and means with SD were used to describe the data. The Kaplan- Meier test was used to estimate the probability of OS and RFS. Survival curves were compared with a log-rank test. Univariate and multivari- ate proportional-hazard Cox regression models were used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs). To ensure the estimability of point estimates in the multi- variate analysis of OS, only variables with more than 50 nonmissing observations and a P value of less than 0.1 in the univariate analysis were in- cluded. In the analysis of RFS, the minimum re- quired number of nonmissing observations was set at 30. Forward stepwise selection at a signif- icance level of 0.1 was used for variable selection in the multivariate models. A P value of less than 0.05 was considered significant. All tests were 2-sided. The analyses were performed with Sta- ta software, version 13.1 (Stata Corporation, Col- lege Station, Texas, United States).
RESULTS The study included 43 women and 23 men at a mean (SD) age of 49 (14.2) years and 55.4 (12.4) years, respectively. Patients aged 50 years or older more often had stages III and IV disease. Of all tumors, 58.9% were hormon- ally active, mainly with overproduction of corti- sol (93%). Only 2 patients had hyperandrogen- ism alone. One woman and one man had hyperes- trogenism coexisting with excessive cortisol lev- els. Mitotane was administered in 53 patients af- ter surgery as an adjuvant treatment; 4 patients with an inoperable tumor received mitotane as a palliative treatment; 7 patients (3 with stage II and 4 with stage III ACC) did not receive mito- tane treatment or any other therapy (1 patient in this group had an inoperable tumor). For the 2 re- maining patients (out of 66), data were missing. The mean (SD) time of mitotane treatment was 31.2 (24) months. No patient received radiother- apy; 4 patients who received mitotane after sur- gery (3 patients with stage IV and 1 patient with stage III) were also treated with chemotherapy.
Overall survival The median OS was 78.19 months for stages I + II, 22.95 months for stage III, 19.54 months for stage IV, and 43.5 months for all the ENSAT stages. The overall 5-year survival was 75%, 73%, 27%, and 0% for stages I, II, III, and IV, respectively. The 5-year survival rate for stage III reached 32% when only operable tumors
were included. The 2-year and 5-year OS for all stages was 66% and 46%, respectively. Death was reported for 85.7% of the patients who did not receive mitotane and 49.1% of the patients who received mitotane; the 5-year survival rate was 28.6% and 48.2%, respectively.
The results of the univariate and multivari- ate analyses of prognostic factors of OS are pre- sented in TABLE 2. In the univariate analysis, old- er age, advanced stage (FIGURE 1), higher Ki67 in- dex (FIGURE 2), higher mitotic index, and margin status R2 were associated with a decreased OS. Age as a continuous variable was independent- ly associated with OS in the multivariate analy- sis (HR, 1.09; P = 0.001). Patients aged 50 years or older had a higher risk of death. The 5-year survival rate for patients younger than 50 years old was 66.9% (95% CI, 44.2-82.1), compared with 29.3% (95% CI, 14.1-46.3) for patients aged 50 years or older (P = 0.004). In the multivariate analysis (of >50 nonmissing observations), other factors remained independently associated with poorer prognosis, such as stage IV (HR, 6.65; P = 0.01) and margin status R2 (HR, 4.3; P = 0.03). Patients treated with mitotane had improved OS both in the univariate (HR, 0.46; P = 0.09) and multivariate analyses (HR, 0.29; P = 0.04). These results were observed even after excluding 4 pa- tients who received both mitotane treatment and chemotherapy. Interestingly, there was no dif- ference in OS between stages I + II and stage III (HR, 1.62; P = 0.4) in the multivariate analysis.
In the univariate analysis, HR for death was 1.03 per 1% increase in the Ki67 index (P = 0.003) and 3.19 for the Ki67 index of 10% or higher (P = 0.01). The 5-year survival of patients with a Ki67 index of less than 10% differed from that in patients with a Ki67 index of 10% or high- er (66.8% vs 36.2%, respectively, P = 0.01). Al- though, the Ki67 index was significant in the uni- variate analysis, in the forward stepwise analysis for variable selection in the multivariate model it did not reach the 0.1-significance level, thus it was not included.
In the univariate analysis, HR for death was 7.91 (P = 0.002) for a mitotic index of 20/50 HPF or higher. The 5-year survival rate was 79.8% for a mitotic index of 20/50 HPF or higher com- pared with 36.3% for a mitotic index of less than 20/50 HPF (P <0.001). However, because the mul- tivariate analysis was performed for more than 50 nonmissing observations, this prognostic fac- tor was not included.
Recurrence-free survival Twenty patients suffered from disease recurrence after potentially curative surgery (RO): 1 patient (25%) with stage I, 12 pa- tients (46%) with stage II, and 9 patients (45%) with stage III ACC. The median probability of RFS was 101.1 months.
The results of the univariate and multivariate analyses of the prognostic factors of RFS after cu- rative surgery are presented in TABLE 3. In the uni- variate analysis, male sex, higher Ki67 index as
| Variable | N = 66 | N+ | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |||
| Age, yª | 66 | 1.06 | 1.03-1.09 | <0.001 | 1.09 | 1.03-1.15 | 0.001 | |
| Male sex | 66 | 23 | 1.83 | 0.91-3.68 | 0.09 | |||
| Hormonal activity | 56 | 33 | 1.85 | 0.82-4.18 | 0.14 | |||
| Tumor sizeª | 63 | 1.01 | 1.00-1.01 | 0.12 | ||||
| Tumor size ≥10 cm | 63 | 37 | 1.25 | 0.61-2.57 | 0.54 | |||
| ENSAT stage | 66 | |||||||
| ENSAT stage I + II | 30 | 1.00 | 1.00 | |||||
| ENSAT stage III | 25 | 3.99 | 1.78-8.94 | 0.001 | 1.62 | 0.53-4.99 | 0.40 | |
| ENSAT stage IV | 11 | 7.31 | 2.60-0.52 | <0.001 | 6.65 | 1.45-30.1 | 0.01 | |
| Ki67 indexª | 56 | 1.03 | 1.01-1.04 | 0.003 | ||||
| Ki67 index ≥10% | 56 | 38 | 3.19 | 1.28-7.97 | 0.01 | |||
| Mitotic index per 50 HPFa | 38 | 1.02 | 1.01-1.03 | <0.001 | ||||
| Mitotic index per 50 HPF ≥20 | 38 | 19 | 7.91 | 2.15-9.11 | 0.002 | |||
| Margin status R0 | 50 | 1.00 | 1.00 | |||||
| Margin status R1 | 3 | 0.88 | 0.20-3.79 | 0.86 | 2.08 | 0.39-10.9 | 0.39 | |
| Margin status R2 | 7 | 4.26 | 1.65-1.01 | 0.003 | 4.30 | 1.16-15.9 | 0.03 | |
| Mitotane treatment | 56 | 5 | 0.46 | 0.19-1.12 | 0.09 | 0.29 | 0.09-0.92 | 0.04 |
| Inoperable tumor | 5 | 40.88 | 10.1-165 | <0.001 | ||||
a Continuous variable
Only variables with >50 nonmissing observations and P <0.1 in the univariate analysis were included in the multivariate analysis. Forward stepwise selection at 0.1 significance level was used for variable selection in the multivariate model. “Inoperable tumor” was not included in the multivariate analysis as it may overlap with stage.
Abbreviations: CI, confidence interval; HR, hazard ratio; N+, number of patients who met the given criteria; others, see TABLE 1
a continuous variable, higher mitotic index, and no mitotane treatment were associated with decreased RFS. In the multivariate analysis (of >30 nonmissing observations), only male sex was associated with reduced RFS (HR, 4.44; P = 0.03), while mitotane treatment was associat- ed with prolonged RFS (HR, 0.15; P = 0.01). HR for disease recurrence after curative surgery was 1.03 per 1% increase in the Ki67 index, but it did not reach significance. The Ki67 index as a cate- gorized variable was not associated with longer RFS (FIGURE 3), probably due to the small number of events. Interestingly, patients with stage III ACC had the same risk for recurrence as patients with stage I or II (HR, 1.62; P = 0.30).
Patients defined as “high-risk” according to the ESMO16 were not found to be at higher risk of disease relapse (HR, 2.02; P = 0.39).
DISCUSSION The present study is the largest analysis of a cohort of Polish patients with ACC, in which numerous clinical and histopatholog- ic prognostic factors as well as treatment results were analyzed. The Ki67 index was associated with reduced OS (as a continuous and catego- rized variable) and RFS (as a continuous vari- able) in the univariate analysis. These results con- firm recently published data showing that Ki67 is the major prognostic factor of OS and RFS.10 In our series the Ki67 index was not included in
the multivariate model of OS, as it did not reach the 0.1 significance level in the forward stepwise selection. As for the multivariate analysis of RFS, Ki67 did not reach significance (HR, 1.03; P = 0.1), probably due to the small number of events. There was a marked difference in the 5-year sur- vival rates: 66.8% for Ki67 <10% vs 36.2% for Ki67 ≥10% (P = 0.01). The mitotic index was also reported to be useful in outcome prediction.19 In our series the index was identified as a prognostic factor of OS in the univariate analysis, and there was a notable difference in the 5-year survival rates (79.8% for the mitotic index <20/50 HPF vs 36.3% for the mitotic index ≥20/50 HPF, P = 0.001). However, too many missing observations and too small a number of events made it impossi- ble to include this factor in the multivariate anal- ysis. The higher mitotic index was strongly associ- ated with decreased RFS in the univariate analy- sis (TABLE 3), and the HR for death reached 4.79 (P = 0.03) for the mitotic index of 20/50 HPF or higher. There was significant difference in 2-year RFS rates: 93.3% and 66.7% for the mitotic in- dex of less than 20/50 HPF and of 20/50 HPF or higher (P = 0.02), respectively. However, due to more than 30 missing observations this fac- tor was not included in the multivariate analysis. As in the case of the lower Ki67, there was a clear tendency for improved OS and RFS in the case of the lower mitotic index. Both the Ki67 and
Log-rank P <0.001
1.00
0.75
Stage I+II
Probability of OS
0.50
Stage III
0.25
Stage IV
0.00
0
12
24
36
48
60
72
84
Analysis time, mo
Number at risk
I or II
30
27
23
18
16
15
10
6
III
25
16
10
8
5
5
4
3
IV
11
4
3
1
0
0
0
0
1.00
Log-rank P = 0.009
0.75
Ki67 <10%
Probability of OS
0.50
Ki67≥10%
0.25
0.00
0
12
24
36
48
60
72
84
Analysis time, mo
Number at risk
<10%
18
17
16
12
9
8
6
4
≥10%
38
23
14
10
8
8
5
3
mitotic indices should be an obligatory part of every histopathologic report of ACC as they may have strong prognostic value.
In the present study, the median probability of OS was 43.5 months and the 5-year OS was 46%, which is comparable to other reports.1,3,4,6,7 However, the authors of one of the latest stud- ies showed that the 5-year survival rate can reach over 90% when patients with stage II are treat- ed with mitotane and followed prospectively by specialized centers.3 In our cohort, 5-year OS for stage II ACC reached 73%, which is better than in previous series that reported a range from 58% to 61%.6,8 Interestingly, despite the noticeable dif- ference in the 5-year survival rates between stag- es I + II and stage III (73.2% vs 27%, respective- ly, P <0.001), stage III was not associated with worse OS in the multivariate analysis (HR 0.73,
P = 0.68) probably due to the small size of our co- hort. Only for stage IV (metastasis at initial pre- sentation), OS was significantly decreased. As for RFS, there was no significant difference in the 2-year survival rate between stages I + II and III (58% and 84.7%, respectively, P = 0.30), and the ENSAT stage was not found to be a prognos- tic factor of RFS in the univariate analysis. These results, again, may be related to the small size of our cohort or the fact that other factors may have a greater influence on OS and RFS than stage (eg, Ki67 or mitotane treatment). Such a good out- come in stage II in our cohort (5-year survival rate of 73%) may be related to the fact that 88% of patients with stage II received adjuvant mito- tane treatment after a potentially curative sur- gery (R0). The results of the present study show that mitotane treatment may be associated with
| Variable | N = 41 | N+ | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | |||
| Age, y | 41 | 1.03 | 0.99-1.07 | 0.12 | ||||
| Male sex | 41 | 13 | 4.03 | 1.48-11 | 0.01 | 4.44 | 1.12-7.54 | 0.03 |
| Hormonal activity | 34 | 16 | 1.53 | 0.52-4.55 | 0.44 | |||
| Tumor sizeª | 39 | 1.00 | 0.99-1.01 | 0.51 | ||||
| Tumor size ≥100 mm | 39 | 18 | 1.27 | 0.46-3.48 | 0.64 | |||
| ENSAT stage | 41 | |||||||
| ENSAT stage I or II | 28 | 1.00 | ||||||
| ENSAT stage III | 13 | 1.62 | 0.65-4.08 | 0.30 | ||||
| Ki67 indexª | c | 1.03 | 1.00-1.06 | 0.03 | 1.03 | 1.00-1.06 | 0.1 | |
| Ki67 index ≥10% | 34 | 20 | 2.09 | 0.64-6.83 | 0.22 | |||
| Mitotic index per 50 HPFª | 26 | 1.05 | 1.01-1.09 | 0.01 | ||||
| Mitotic index per 50 HPF ≥20 | 26 | 9 | 4.79 | 1.13-20.38 | 0.03 | |||
| Mitotane treatment | 41 | 36 | 0.34 | 0.12-0.96 | 0.04 | 0.15 | 0.04-0.56 | 0.01 |
a
Continuous variable
Only variables with >30 nonmissing observations and P <0.1 in the univariate analysis were included in the multivariate analysis. Forward stepwise selection at 0.1 significance level was used for variable selection in the multivariate model.
Abbreviations: see TABLES 1 and 2
1.00
Log-rank P = 0.21
Ki67 <10%
0.75
Probability of RFS
0.50
Ki67≥10%
0.25
0.00
| 0 | 12 | 24 | 36 | 48 | 60 | 72 | 84 | |
|---|---|---|---|---|---|---|---|---|
| Analysis time, mo | ||||||||
| Number at risk | ||||||||
| <10% | 14 | 14 | 13 | 9 | 7 | 6 | 4 | 3 |
| ≥10% | 20 | 14 | 10 | 10 | 7 | 7 | 4 | 3 |
prolonged OS and RFS in patients with ACC, re- gardless of the tumor stage. These findings are consistent with previous reports.13,20-22 Howev- er, in our study, after potentially curative sur- gery only 6 patients were not treated with mi- totane (vs 53 patients who received this treat- ment). Despite the fact that the percentage of relapse is high (27% and 46% for stage I and II, respectively),14 and numerous reports show that mitotane may improve outcome in stages I and II,3,13 this treatment is not mandatory in early stages of ACC.16 This is probably because those results have not been confirmed in randomized trials. There has been only one report recently
suggesting that mitotane treatment is associat- ed with decreased OS and RFS in the univariate analysis (Cox proportional hazards analysis), but these results were no longer observed in the mul- tivariate analysis.23 However, this was a retrospec- tive analysis, which used the TNM staging24 in- stead of the ENSAT staging system and the pa- tient selection for treatment was biased. In pa- tients who received mitotane, the authors report- ed more advanced stage, more hormonally active tumors, more adjuvant chemotherapy and/or ra- diotherapy (factors which are per se associated with worse prognosis), compared with patients not receiving mitotane treatment.23 Hopefully,
data from the first randomized trial (ADIUVO) on evaluating mitotane in the treatment of stages I to III ACC will soon be published, and mitotane may finally find its way to routine clinical prac- tice. Based on our long experience in the manage- ment of ACC,17,20,25-27 we recommend mitotane in every patient with ACC who is tolerant to this type of treatment.
In line with our findings, other studies also described older age7,14 as a prognostic factor of worse survival. A recent report proposed a mod- ification of the ENSAT staging system that would include patient age (>55 years of age).28 In our study, patients aged 50 years or older had more advanced stage of the disease, which may indi- cate a delayed diagnosis in older patients not re- lated to the functional status of ACC (there was no difference between both age groups in tumor hormonal activity, P = 0.17). Another important prognostic factor is the margin status after sur- gery. It was previously shown that 5-year survival rates are lower for patients with microscopically (21%) and macroscopically (10%) involved mar- gins, compared with uninvolved margins (46%).9 In the present study, margin status R2 was re- lated to poorer OS in the multivariate analysis, but margin status R1 did not reach significance, probably due to the small number of events (only 3 patients).
Similarly to a previous study,19 tumor size was not associated with reduced OS or RFS. Except one report,12 most authors claimed that patients with cortisol-secreting tumors had poorer prog- nosis.13-15 In the present study, hormonal activi- ty was not related to shorter OS or RFS.
The strength of the present study is follow-up duration from 2002 to 2015, which allowed us to obtain reliable data. On the other hand, the major limitation is a relatively small number of partic- ipants, and as this is a retrospective study, some of the medical data are incomplete. Moreover, patients were recruited from different centers, so methods of follow-up were inconsistent. Un- fortunately, we do not have information on mi- totane concentrations as they were not provided. For further research, it is crucial to standardize the monitoring process. It is also necessary that the mitotane treatment is fully controlled with plasma levels within the therapeutic range to en- sure that the therapy is adequate and safe. How- ever, ACC is extremely rare and most of the rele- vant information about the course of the disease and treatment results come from retrospective analyses of national registries.3,5,6,8,10
In conclusion, we identified prognostic factors of survival in patients with ACC: older age, stage IV ACC, margin status R2, no mitotane treatment, and higher Ki67 and mitotic indices. These factors should be considered when planning the manage- ment after surgery. Mitotane treatment may be associated with better outcomes in patients with ACC regardless of the tumor stage. Due to the ag- gressive behavior of ACC and high percentage
of relapse, more studies are needed to help im- prove survival.
CONTRIBUTION STATEMENT KMN and LP de- signed the study. KMN, RS, AC, AŁ-Sz, UA, LK, MO, KR-P, WZ, and LP were involved in data col- lection. KMN analyzed the data. All authors edited and approved the final version of the manuscript.
OPEN ACCESS This is an Open Access article dis- tributed under the terms of the Creative Com- mons AttributionNonCommercialShareAlike 4.0 International License (CC BY-NC-SA 4.0), allowing third parties to copy and redistribute the material in any medium or format and to re- mix, transform, and build upon the material, pro- vided the original work is properly cited, distrib- uted under the same license, and used for non- commercial purposes only. For commercial use, please contact the journal office at pamw@mp.pl.
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