Adv Ther (2019) 36:2756–2768

https://doi.org/10.1007/s12325-019-01050-0

ORIGINAL RESEARCH

Prognostic Role of Ki-67 in Adrenocortical Carcinoma

After Primary Resection: A Retrospective Mono-
Institutional Study
Fuxun Zhang . Fan Zhang . Zhihong Liu . Kan Wu .
Yuchun Zhu . Yiping Lu

Received: June 17, 2019 / Published online: August 30, 2019

Ó Springer Healthcare Ltd., part of Springer Nature 2019

ABSTRACT hazard ratios for univariate and multivariate

analyses.
Introduction: Adrenocortical carcinoma (ACC) Results: Of the 66 patients, recurrence was
is a rare malignancy with poor prognosis. It is observed in 30 patients (45.5%) and 26 patients
vitally important to predict prognosis and restrict (39.4%) died of progressive ACC. The evaluated
unnecessary adjuvant treatments for patients median overall survival (OS) of the
with ACC. This study aims to confirm the prog- entire study population was 16.5 (range 1–104)
nostic value of Ki-67 and provide a prognostic months and recurrence-free survival (RFS) was
evaluation on ACC after primary surgery. 9.0 (range 0–104) months. Increased Ki-67
Methods: A total of 66 patients satisfied the expression ([ 20% and [ 3%) was negatively
inclusion criteria and their complete data were correlated with OS and RFS (chi-square, P = 0.006
collected and reviewed. The correlation and 0.044, respectively). In multivariate analysis,
between Ki-67 index and clinicopathologic the Ki-67 index with 20% and 3% cutoff as an
variables was analyzed using chi-square tests independent prognostic factor for OS and RFS
and Pearson’s or Spearman’s test. Survival was validated [hazard ratio (HR) 3.289; 95% CI
curves were generated by Kaplan–Meier analysis 1.345–8.042; P = 0.009 and HR 4.471; 95% CI
and compared with the log-rank test. The Cox 1.086–18.410; P = 0.038, respectively].
regression model was performed to estimate Conclusions: Ki-67 is a reliable, convenient,
and independent prognostic marker for ACC.
Yuchun Zhu and Yiping Lu are co-corresponding Additionally, as an indicator with a divergent
authors of this article. prognostic role at different cutoff values (20%
Enhanced Digital Features To view enhanced digital and 3%), Ki-67 could be used for stratifying
features for this article go to https://doi.org/10.6084/ patients with a high risk of death or rapid
m9.figshare.9198170. recurrence.

Fuxun Zhang
Fan Zhang
Z. Liu
K. Wu

Keywords: Adrenocortical carcinoma; Cutoff
Y. Zhu (&)
Y. Lu (&)
Department of Urology, Institute of Urology, West value; Ki-67; Marker; Prognosis
China Hospital, Sichuan University, Chengdu,
Sichuan, China
e-mail: [email protected] INTRODUCTION
Y. Lu
e-mail: [email protected] Adrenocortical carcinoma (ACC) is a rare
malignancy with an estimated incidence of
Adv Ther (2019) 36:2756–2768 2757

1.0–2.0 cases per 1 million population per year mitotic spindle after nuclear envelope disassem-
and has one of the poorest prognoses among all bly [12]. As an antigen highly expressed in
solid tumors [1, 2]. Although complete resec- cycling cells but significantly downregulated in
tion is the mainstay in ACC therapy and most resting cells, Ki-67 was identified as an important
patients with localized tumor are potentially and well-established proliferation marker for
curable, disease relapse is a common occurrence tumor grade and prognosis in many other
and devastatingly influences the life expectancy malignances in previous studies [13]. Thus,
[3]. Mitotane, an effective drug for patients with increasing attention has been paid to prognostic
advanced ACC, is used in an adjuvant setting to research on Ki-67 in various tumors owing to its
reduce recurrence on the basis of retrospective availability and long-standing clinical utility.
evidence. However, the efficacy of mitotane has As a consequence, this study aimed to con-
never been assessed in a randomized trial and it firm convenient and affordable prognostic
has many side effects including the probable biomarkers and additionally provide prognostic
disturbance of metabolism of hormones and evaluation for patients with ACC after primary
drugs [4, 5]. Furthermore, despite the fact that resection who might be at high risk of rapid
some reports have shown the relationship be- recurrence or death. In this setting, we exam-
tween radiotherapy and prevention of local ined detailed clinical and histopathological data
recurrence [6], many studies indicate the inef- on 66 ACC patients to determine whether Ki-67
fectiveness of radiotherapy and consider ACC as has prognostic value in patients with this
insensitive to radical therapy [7, 8]. Thus, the infrequent malignancy.
current treatment model with uncertain effi-
cacy, restriction to toxic drugs, and disease
recrudesce still remains a challenge for METHODS
researchers worldwide. Therefore, it would be of
great importance to predict prognosis and Patients
determinate high-risk patients by utilizing
postoperative molecular markers from routine We reviewed the medical records of patients
diagnostic workup. Meanwhile, necessary diagnosed with ACC between January 1, 2009
restriction on adjuvant approaches with and December 31, 2017 at the West China
potential adverse effects should be considered Hospital, Sichuan University. The patients in our
in ACC patients with insensitivity to therapy or study had to meet the following inclusion crite-
low risk of rapid relapse. ria: pathologically confirmed diagnosis of ACC,
Although histopathological scoring systems available laboratory results of hematologic and
have been used for a long time to discriminate biochemical function, no medical history of any
benign and malignant adrenal tumors, their other tumor, no adjuvant therapy with anti-
associations with predictive value have not neoplastic drugs prior to the first operation,
been fully investigated and established [9, 10]. available preoperative and postoperative imag-
Recent studies inspected the diagnostic and ing, and accessible data on tumor inva-
prognostic value of biomarkers for ACC and sion and surgical margin status judged on the
suggested that not all of them were informative basis of surgical and pathological report (detailed
and able to predict unwanted outcome. Mean- clinical information included in this study is
while, even for reportedly extensively resear- provided in Table 1). All morphological diagno-
ched markers applied in prognostic tests, they sis accepted re-evaluation according to the Weiss
are still far from being used in routine practice criteria and Ki-67 (MIB1) score was assessed by
because of their expense and inaccessibility experienced pathologists from the same depart-
[10, 11]. ment in the West China Hospital. Staging, based
Ki-67, a proliferation protein and pivotal on imaging assessed by independent reviewers,
component of the mitotic chromosome periph- was confirmed by the findings at surgery using
ery, is essential to enable independent chromo- the American Joint Committee on Cancer
some motility and efficient interactions with the (AJCC) 7th edition. Moreover, follow-up was not
2758 Adv Ther (2019) 36:2756–2768

Table 1 Clinicopathological characteristics of the study suspended until death occurred or to the end of
population December 2017.
Feature N = 66
Study Protocol and Statistical Analysis
Age (years) [median (range)] 44 (2–79)
Gender [n (%)] This study was clinician-initiated, retrospective,
and conducted at one of the professional med-
Male 29 (43.9)
ical centers for the treatment of adrenal tumor
Female 37 (56.1) in China. Patients’ data were collected at the
Side [n (%)] West China Hospital. No commercial entity was
involved in this research. The primary endpoint
Right 38 (57.6) was overall survival (OS) defined as the interval
Left 28 (42.4) from the date of first surgery to the date of last
follow-up or death caused by any reason, and
Comorbidities [n (%)] the secondary was recurrence-free survival (RFS)
Yes 16 (24.2) calculated as the time from primary operation
to diagnosis of recurrence for relapsed patients
No 50 (75.8)
or to last follow-up for recurrence-free patients.
Function [n (%)] Besides, recurrence was defined as the radio-
logical detection of a neoplastic lesion follow-
Yes 28 (42.4)
ing primary resection during the follow-up,
No 38 (57.6) which was adjudicated by independent
Albumin (mean ± SD) (g/dL) 40.6 ± 5.1 reviewers.
Database management and all statistical
Globulin (mean ± SD) (g/dL) 21.4 ± 5.2 analyses were performed using the SPSS 23.0
Diameter of tumor (cm) [median (range)] 8.1 (1–20) statistical analysis software (IBM, New York,
USA). Mean value and standard deviation or
Tumor stage [n (%)] median and ranges were computed for contin-
I 8 (12.1) uous variables. Rates or proportions were com-
puted for categorical variables. The correlation
II 35 (53.0)
between Ki-67 index and clinicopathologic
III 19 (28.8) variables was analyzed using chi-square tests for
IV 4 (6.1) categorical variables and Pearson’s or Spear-
man’s test for continuous variables. There has
Modus operandi [n (%)] been little consensus in selection of Ki-67 cutoff
Open 46 (69.7) points, and the predictions regarding OS and
RFS in this study have been based on a wide
Laparoscopy 20 (30.3) range of Ki-67 score from 0% to 90%. In light of
Post-relapse adjuvant treatment [n (%)] this, Ki-67 was modelled as a binary variable
and exploratively grouped by cutoff 1–5% with
Treated 14 (21.2)
equidistant increases of 5% or 10%. Survival
Untreated 52 (78.8) curves were generated by Kaplan–Meier analysis
and compared with the log-rank test. The Cox
Recurrence [n (%)] 30 (45.5)
regression model was used to estimate hazard
Death [n (%)] 26 (39.4) ratios for univariate and multivariate analyses.
Levels of statistical significance were set at
SD standard deviation
P \ 0.05. All P values were two-sided and 95%
CIs and P values were based on X2 statistics with
one degree of freedom.
Adv Ther (2019) 36:2756–2768 2759

Fig. 1 Flow diagram

Compliance with Ethics Guidelines medical data were collected and reviewed
(Fig. 1). During the thorough follow-up of all
This article is based on previously collected data the patients, relapse was observed in 30 patients
and does not contain any new studies with (45.5%) while 26 patients (39.4%) died of pro-
human participants or animals performed by gressive ACC. The evaluated median OS of the
any of the authors. The institutional review entire study population was 16.5 (range 1–104)
board of West China Hospital had approved this months and RFS was 9.0 (range 0–104) months
study and all patients included in this study (characteristics of these patients including
provided informed consent for the use and recurrence and death are provided in Table 1).
publication of their data. Outcome-affecting clinical characteristics
were preoperative albumin, modus operandi,
diameter of tumor, and Ki-67 index analyzed as
RESULTS a binary variable. However, only the Ki-67 index
with 20% cutoff as an independent prognostic
Patients and Clinical Prognostic Factors factor for OS and 3% cutoff for RFS had been
confirmed utilizing multivariate the Cox model
A total of 78 patients were screened for this (P = 0.009 and 0.038, respectively). Interest-
study. After the exclusion of 12 patients who ingly, Ki-67 index was notably related to OS
were lost to follow-up, provided incomplete with the cutoff of 20% (chi-square, P = 0.006)
medical records, or provided incomplete but irrelevant to it with the cutoff of 3% (chi-
pathological data or imaging assessment, 66 square, P = 0.254). Similarly, significant corre-
patients satisfied the inclusion criteria and their lation was observed between Ki-67 index with
2760 Adv Ther (2019) 36:2756–2768

Table 2 Associations of Ki-67 with disease variables

Variable Ki-67 index Chi-square P value
£ 20% > 20%
Total 54 (81.8) 12 (18.2)
Age (years) [n (%)]
B 45 28 (42.4) 8 (12.1) 0.869 0.351
[ 45 26 (39.4) 4 (6.1)
Gender [n (%)]
Male 23 (34.8) 6 (9.1) 0.219 0.640
Female 31 (47.0) 6 (9.1)
Side [n (%)]
Right 30 (45.5) 8 (12.1) 0.496 0.481
Left 24 (36.4) 4 (6.1)
Comorbidities [n (%)]
Yes 15 (22.7) 1 (1.5) 2.021 0.155
No 39 (59.1) 11 (16.7)
Function [n (%)]
Yes 24 (36.4) 4 (6.1) 0.496 0.481
No 30 (45.5) 8 (12.1)
Tumor stage [n (%)]
I/II 38 (57.6) 5 (7.6) 3.563 0.059
III/IV 16 (24.2) 7 (10.6)
Modus operandi [n (%)]
Open 36 (54.5) 10 (15.2) 1.291 0.256
Laparoscopy 18 (27.3) 2 (3.0)
Post-relapse adjuvant treatment [n (%)]
Treated 12 (18.2) 2 (3.0) 0.181 0.670
Untreated 42 (63.6) 10 (15.2)
Recurrence [n (%)]
Yes 26 (39.4) 4 (6.1) 0.869 0.351
No 28 (42.4) 8 (12.1)
Survival [n (%)]
Yes 36 (54.5) 4 (6.1) 4.569 0.033
No 18 (27.3) 8 (12.1)
Albumin 0.771
Adv Ther (2019) 36:2756–2768 2761

Table 2 continued
Variable Ki-67 index Chi-square P value
£ 20% > 20%

Globulin 0.884
Diameter of tumor 0.474
Bold figures indicate statistical significance at P \ 0.05

the cutoff of 3% and RFS (chi-square, P = 0.044), groups was 18 months (range 1–104 months)
but irrelevance between Ki-67 index with the and 14 months (range 2–73 months) respec-
cutoff of 20% and RFS (chi-square, P = 0.985) tively. Kaplan–Meier survival curves for Ki-67 in
(the origin of the material used for analysis is two groups (B 20% vs [ 20%) showed a
outlined in Table 3). remarkable difference (P = 0.006, Fig. 2a).
On the other hand, two of 12 patients with
Prognostic Role of Ki-67 Index Ki-67 score B 3% suffered recurrence and the
with Diverse Cutoffs median RFS for this group was 21.5 months
(range 1–104 months); 28 of 54 patients with
Increased Ki-67 expression ([ 20% and [ 3%) Ki-67 score [3% relapsed and median RFS was
was negatively correlated with OS and RFS in 8 months (range 0–76 months). Statistical cor-
patients with ACC (chi-square, P = 0.006 and relation was found between the Ki-67 index
0.044, respectively). No prognostic effect of age, with a 3% cutoff and disease recurrence in
gender, side, globulin, secretion, stage, post-re- univariate and multivariate analyses using the
lapse adjuvant treatment, and comorbidity Cox regression model (P = 0.044 and 0.038,
including diabetes and hypertension was respectively) (Tables 3, 4; Fig. 2b). We also
observed in univariate analysis (Table 3). A total assessed Ki-67 score as a continuous variable
of 54 cases were in the low Ki-67 group (B 20%) and categorical variable with diverse cutoff
with 18 deaths (33.3%) and 12 cases in the high points (2%, 4%, 10%, 15%, 25%, and 30%);
Ki-67 group ([ 20%) with 8 deaths (66.7%) however, no significant difference was observed
(Table 2), while the estimated median OS in two in corresponding groups (Table 3).

Fig. 2 Kaplan–Meier curves showed a significantly decreased overall survival in group with Ki-67 [ 20% (a), and cases
with Ki-67 expression [ 3% recurred rapidly and had shorter recurrence-free survival (b)
2762 Adv Ther (2019) 36:2756–2768

Table 3 Univariate analysis of prognostic factors for OS and RFS

Variable Univariate analysis for OS Univariate analysis for RFS
HR (95%CI) P value HR (95%CI) P value
1 (ref) 1 (ref)
Age
B 45 0.917 (0.420–2.002) 0.828 0.781 (0.375–1.624) 0.508
[ 45
Gender
Male 1.177 (0.539–2.573) 0.682 1.661 (0.788–3.500) 0.182
Female
Side
Right 0.740 (0.332–1.648) 0.461 0.971 (0.461–2.045) 0.938
Left
Comorbidities
Yes 0.918 (0.366–2.301) 0.855 1.296 (0.572–2.938) 0.534
No
Function
Yes 0.979 (0.449–2.134) 0.958 0.808 (0.384–1.701) 0.575
No
Tumor stage
I/II 1.609 (0.733–3.533) 0.236 1.539 (0.724–3.268) 0.262
III/IV
Diameter of tumor 1.108 (1.007–1.219) 0.035 0.973 (0.882–1.074) 0.594
Modus operandi
Open 0.337 (0.116–0.979) 0.046 1.121 (0.527–2.383) 0.767
Laparoscopy
Postoperative adjuvant treatment
Treated 0.839 (0.335–2.098) 0.707 – –
Untreated
Recurrence
Yes 0.921 (0.424–2.000) 0.835 – –
No
Ki-67 index
3% cutoff 1.652 (0.698–3.911) 0.254 4.263 (1.037–17.531) 0.044
5% cutoff 0.765 (0.326–1.793) 0.538 2.979 (0.899–9.868) 0.074*
Adv Ther (2019) 36:2756–2768 2763

Table 3 continued
Variable Univariate analysis for OS Univariate analysis for RFS
HR (95%CI)1 (ref) P value HR (95%CI)1 (ref) P value

10% cutoff 1.980 (0.879–4.460) 0.099* 1.364 (0.631–2.947) 0.430

20% cutoff 3.320 (1.402–7.861) 0.006 0.990 (0.342–2.863) 0.985
30% cutoff 2.162 (0.803–5.821) 0.127 0.903 (0.272–2.997) 0.868
Albumin 0.953 (0.88–1.031) 0.228 0.940 (0.875–1.011) 0.094*
Globulin 0.994 (0.928–1.066) 0.874 0.970 (0.908–1.037) 0.378
Bold figures indicate statistical significance at P \ 0.05, *could be treated as statistically significant adjusted significant level
(a = 0.10)
OS overall survival, RFS recurrence-free survival, HR hazard ratio, 1 (ref) 1 degree of freedom, CI confidence interval

Table 4 Multivariate analysis of the Cox regression model model on account of inadequacy of statisti-
for OS and RFS cal power and predictive value (Table 4; Fig. 3).
Parameter HR [1 (ref)] 95% CI P value
Analysis for OS DISCUSSION
Diameter of 1.056 0.949–1.174 0.319
Treatment and prognosis for ACC have not
tumor significantly improved in recent years. In this
Modus operandi 0.403 0.126–1.297 0.128 disappointing scenario, the potential prognos-
tic role of molecular biomarkers should be fur-
20%-cutoff 3.289 1.345–8.042 0.009
ther investigated and immunotherapy should
Ki-67 be considered one of the most promising
Analysis for RFS approaches in the future [14]. At the same time,
although great progress has been made in
Albumin 0.930 0.861–1.005 0.065*
exploration on altered genes and emerging
Ki-67 with 3% 4.471 1.086–18.410 0.038 protein markers for ACC over the last decade,
cutoff recent guidelines still emphasize the combina-
tion of clinical parameters and molecular
Ki-67 with 5% 2.993 0.903–9.923 0.073*
markers to ameliorate the prognosis of this rare
cutoff malignancy [15]. However, easy and cost-effec-
Bold figures indicate statistical significance at P \ 0.05, tive biomarkers related to prognosis
*could be treated as statistically significant at adjusted sig- have been recognized as a rarity [15, 16].
nificant level (a = 0.10) Ki-67, the most promising immunohisto-
OS overall survival, RFS recurrence-free survival, HR haz chemical proliferation marker identified so far,
ard ratio, 1 (ref) 1 degree of freedom, CI confidence interval has been shown to play a prognostic role in
several malignancies with various tissue
derivation [17]. In this setting, higher Ki-67
In Cox multivariate analysis, the dichoto- expression was considered to be associated with
mous Ki-67 index with the cutoff of 20% and unfavorable clinical outcomes in many cancers
3% as independent prognostic factors for OS [18]. Moreover, recent studies compared Ki-67
and RFS was validated (HR 3.289; 95% CI with other predictors at prognostic value and
1.345–8.042; P = 0.009 and HR 4.471; 95% CI regarded Ki-67 as a more powerful biomarker
1.086–18.410; P = 0.038) (Fig. 3). The covariate carrying significantly prognostic information
extent of disease was excluded from the final [18, 19]. High expression of Ki-67 also has a
2764 Adv Ther (2019) 36:2756–2768

Fig. 3 Hazard ratio for prognostic indicators analyzed using a Cox proportional hazard model. Horizontal bars represent
95% confidence intervals

direct correlation with tumor size, grade, and value of Ki-67 score applied in prognostic study
increased mortality [20, 21]. on ACC should be determined as well.
As a result of the rarity of ACC, the associa- In this study, we evaluated the clinical-
tion between molecular biomarkers and recur- pathological associations and the prognostic
rence or overall survival has not been defined role of Ki-67 in a consecutive mono-institu-
adequately compared with other cancers in tional series of ACCs and found that high Ki-67
clinical practice. To our knowledge, few studies expression was associated with worse outcomes.
analyzed the prognostic role of Ki-67 in ACC In the current study, Ki-67 score was analyzed as
and little data on clinical risk of tumor progres- a dichotomous variable for its prognostic role at
sion were available in China. Assessment of Ki- diverse cutoffs and served as a prognostic dis-
67 in previous studies has prompted specula- criminator to distinguish patients with different
tion that Ki-67 should be considered the most outcomes. Our work showed that ACC patients
important predictor in patients following com- with Ki-67 expression less than or equal to 20%
plete resection [22]. However, the evi- had better OS compared those who maintained
dence in recent studies was flawed by several Ki-67 expression greater than 20%; analogously,
limitations from heterogeneous data sources, patients whose tumors had Ki-67 expression less
such as uniformly defined OS and RFS, diverse than or equal to 3% had better RFS and delayed
treatment measures in different patients, vari- recurrence. In this sense, we confirmed that the
ability of Ki-67 index evaluated by different Ki-67 index with varied cutoffs has different
pathologists in different medical institutions, prognostic value for mortality and rapid recur-
and obvious variation in baseline characteristics rence (Fig. 4). Besides, in univariate analysis for
on account of the large time span in patients RFS, the association between variables and
included [22]. At the same time, varied cutoff relapse was treated as statistically significant at
values of Ki-67 in previous studies may be an adjusted significant level (a = 0.10) because
indicative of the deviation in threshold-value of the rarity of ACC and insufficient sample size
confirmation and histomorphological hetero- (Table 3). Although out results were not as
geneity of ACC. Therefore, an optimized cutoff strong as those in prior reports, we believe that
Adv Ther (2019) 36:2756–2768 2765

Fig. 4 Distribution of recurrent and survival cases in corresponding cohort grouping by Ki-67 score with different cutoff
(3% and 20%, respectively)

Ki-67 score with the 3% cutoff could be an best approach to evaluate the prognosis for ACC
independent predictor of recurrence and continues to fuel debate [23, 27]. Furthermore,
patients with Ki-67 expression greater than 3% although some prognostic predictors such as
may relapse more rapidly (Fig. 2b). surgical margin status, invasion of adjacent
In addition to the Ki-67 index, the prognosis structures, and distant metastasis could be
of ACC had proven to be driven partially by considered as indicators for tumor progression,
other factors, including the presence of age, these predictors seem to be more intuitive and
functionality, tumor stage, metastasis, invasion subjective for experience-varied surgeons and
of adjacent structures, and resection status [23]. also lead to uncertainty. Thus, it is not easy to
Age was defined as a dichotomous variable assess resection status objectively and define the
according to the median in this study which optimal time to perform R0 resection accurately
may be optimal. Although some studies have [23, 28].
indicated that cortisol-secreting ACCs might be In the present study, there was no significant
associated with unwanted prognosis [24, 25], we correlation between Ki-67 index and age, gen-
did not find that functional status was a signif- der, side, comorbidity, adjuvant treatment,
icant prognostic factor. Thus, the functionality functionality, and tumor stage (Table 2). High
of ACC should not preclude surgery and adju- Ki-67 index ([ 20%) was only correlated with
vant treatment. At this point, further investi- overall survival (Table 2). Our study also dis-
gations should be conducted on the correlation covered several factors that might portend
between the magnitude and subtypes of secre- worse prognosis, such as diameter of tumor,
tions and the clinical outcome. In recent stud- modus operandi, and preoperative albumin.
ies, the tumor stage was recognized as the However, no independent prognostic marker
basis of prognostic stratification of ACC, among them was validated in multivariate
underscoring the importance of the T-staging analysis (Table 4).
system [26]. However, the T-stage classification A recent study described Ki-67 as an uncer-
system for ACC is still being revised and the tain predictive marker and indicated that the
2766 Adv Ther (2019) 36:2756–2768

deficiency of uniform quantification and pro- Though our study is retrospective and
liferative heterogeneity of ACC might requires further validation, the rarity of adrenal
place a substantial limitation on its utility [29]. cancer remains the biggest challenge to con-
However, in spite of its small simple size, our ducting a prospective study. As mentioned
study suggested that the Ki-67 index could be above, several studies had aggregated and pro-
deemed as a prognostic parameter in accor- cessed a massive amount of information about
dance with recent data [22, 23]. Meanwhile, ACC patients who underwent treatment at
mono-institutional assessment of Ki-67 may various clinical centers, and it seems that Ki-67
minimize the adverse impact of the confound- is well researched on the basis of the large
ing factors (also known as interobserver or number of patients. However, it is crucial to
interlaboratory variation) such as tissue prepa- highlight that both diversity of demographic
ration, interpretation, scoring, and data analysis characteristics and heterogeneity of merging
which varied at different laboratories and clin- data from different medical institutions
ical centers. should be taken into account judiciously. After
Discrimination between ACC and benign all, statistical robustness depends not only on
adrenocortical tumors is difficult and can be the number of included patients but also
accomplished using multiple histological scores, homogeneity of data. Furthermore, though Ki-
such as the Weiss system or Weiss revisited index. 67 has been considered the most cogent pre-
Our research was limited to evaluate the associ- dictor for ACC thus far [22], it is necessary to
ation between the Weiss score, Ki-67 expression, perform confirmatory research and continu-
and the clinical outcome. However, the Weiss ously collect primary data for clinical and
score had limited prognostic potential and failed prognostic utilization.
to predict all outcomes [10]. This uncertainty is
probably ascribed to interobserver or interlabo-
ratory variation mentioned above and stan- CONCLUSIONS
dardization of applying certain scoring systems
requires further studies. Ki-67 is a reliable, convenient, and independent
The limitations of this study include the prognostic marker for patients with ACC. In this
retrospective nature of its design, 12 patients study, Ki-67 score carried a divergent prognostic
who provided incomplete data were not inclu- role at different cutoffs and should be drawn
ded, and the small sample size with inadequate into treatment flow charts. Additionally, Ki-67
statistical power and inherent biases. On the score with different cutoffs (20% and 3%) could
other hand, the result of our study might be serve as a potential discriminator in prognosti-
influenced by those patients that died from cation models for stratifying patients with high
other causes. Additionally, the recently pub- risk of death or rapid recurrence who should be
lished experience shows that adjuvant treat- provided appropriate treatment options and
ments including radiation therapy and prudent follow-up evaluation. Besides, future
mitotane are associated with improvement of efforts should focus not merely on searching for
clinical outcome [30, 31]. In the present study, a probable malignancy marker but also original
however, only the impact of post-relapse adju- investigations and confirmatory studies suit-
vant treatment was incorporated into analysis able for meta-analysis, aiming at generating
because of the different perspectives on adju- more convincing evidence to improve the
vant strategies, the paucity of accurate data on therapeutic strategies and prognosis in patients
treated cases, and extremely low propor- with this rare disease.
tion of patients who accepted adjuvant treat-
ment after primary resection. All of these factors
may influence the result and confidence. ACKNOWLEDGEMENTS
Therefore, additional cases should be accumu-
lated to elucidate these associations and sup- We thank the participants of the study in
plementary investigations are mandatory. addition to Chuan Zhou and Jiayu Liang for
Adv Ther (2019) 36:2756–2768 2767

their contributions to the collection of data and 3. Kim Y, Margonis GA, Prescott JD, et al. Curative
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Disclosures. All named authors, Fuxun therapy after primary surgical resection in patients
Zhang, Fan Zhang, Zhihong Liu, Kan Wu, with adrenocortical carcinoma. J Clin Endocrinol
Metab. 2013;98:192–7.
Yuchun Zhu, and Yiping Lu, have nothing to
disclose. 8. Atallah S, Al-Assaf H, Xu Y, et al. Adrenocortical
carcinoma: patterns of care and role of adjuvant
Compliance with Ethics Guidelines. This radiation therapy—a population-based study and
article is based on previously collected data and review of the literature. Curr Oncol. 2017;24:
e316–22.
does not contain any new studies with human
participants or animals performed by any of the 9. van’t Sant HP, Bouvy ND, Kazemier G, et al. The
authors. The institutional review board of West prognostic value of two different histopathological
China Hospital had approved this study and all scoring systems for adrenocortical carcinomas.
Histopathology. 2007;51:239–45.
patients included in this study provided
informed consent for the use and publication of 10. Mete O, Gucer H, Kefeli M, et al. Diagnostic and
their data. prognostic biomarkers of adrenalcortical carci-
noma. Am J Surg Pathol. 2017;48:201–13.
Data Availability. The datasets analyzed
11. Zheng S, Cherniack AD, Dewal N, et al. Compre-
during the current study are available from the hensive pan-genomic characterization of adreno-
corresponding author on reasonable request. cortical carcinoma. Cancer Cell. 2016;30:363.

12. Cuylen S, Blaukopf C, Politi AZ, et al. Ki-67 acts as a

biological surfactant to disperse mitotic chromo-
somes. Nature. 2016;535(7611):308–12.
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