Age in combination with gender is a valuable parameter in differential diagnosis of solid pseudopapillary tumors and pancreatic neuroendocrine neoplasm

Abstract

Background
The clinicopathological characteristics of solid pseudopapillary tumor (SPT) and pancreatic neuroendocrine neoplasm (pNEN) are different. We, therefore, systematically investigated the performance of the clinicopathological characteristics in distinguishing SPT from pNEN.

Methods
We collected the cases from the Surveillance, Epidemiology, and End Results Program. The International Classification of Diseases for Oncology, third edition (ICD-O-3) for tumors was used to identify patients with pNEN or patients with SPT. To determine the performance of age in combination with gender in distinguishing SPT from pNEN, a nomogram was developed and the performance of this nomogram was evaluated by the receiver operating characteristic curve and the area under the curve (AUC).

Results
In the training cohort, 563 patients with pNENs and 30 patients with SPTs were recruited. The logistic regression and receiver operating characteristic curves suggest that age, gender, T-stage, N-stage, and M-stage could discriminate SPT and pNEN. The AUC of age, gender, T-stage, N-stage, and M-stage was 0.82, 0.75, 0.65, 0.69, and 0.70, respectively. Based on the nomogram, we observed that the AUC of age and gender is significantly high than that of the T-stage, N-stage, and M-stage.

Conclusions
The present study proposes a non-invasive nomogram that could aid in the differential diagnosis of pNEN and SPT. This might help the clinicians to distinguish SPT from pNEN and choose the appropriate treatments for the patients.

Full text

Wuetal. BMC Endocrine Disorders (2022) 22:255
https://doi.org/10.1186/s12902-022-01164-7
RESEARCH
Age incombination withgender
isavaluable parameter indierential diagnosis
ofsolid pseudopapillary tumors andpancreatic
neuroendocrine neoplasm
Leshuang Wu1,2, Tianle Zou3, Dan Shi3, Huan Cheng2,3, Muhammad Shahbaz3, Muhammad Umar3, Tianfeng Li3,
Xianbin Zhang3, Peng Gong3,4 and Yushan Wei1,5*
Abstract
Background: The clinicopathological characteristics of solid pseudopapillary tumor (SPT) and pancreatic neuroen-
docrine neoplasm (pNEN) are different. We, therefore, systematically investigated the performance of the clinico-
pathological characteristics in distinguishing SPT from pNEN.
Methods: We collected the cases from the Surveillance, Epidemiology, and End Results Program. The International
Classification of Diseases for Oncology, third edition (ICD-O-3) for tumors was used to identify patients with pNEN or
patients with SPT. To determine the performance of age in combination with gender in distinguishing SPT from pNEN,
a nomogram was developed and the performance of this nomogram was evaluated by the receiver operating charac-
teristic curve and the area under the curve (AUC).
Results: In the training cohort, 563 patients with pNENs and 30 patients with SPTs were recruited. The logistic
regression and receiver operating characteristic curves suggest that age, gender, T-stage, N-stage, and M-stage could
discriminate SPT and pNEN. The AUC of age, gender, T-stage, N-stage, and M-stage was 0.82, 0.75, 0.65, 0.69, and 0.70,
respectively. Based on the nomogram, we observed that the AUC of age and gender is significantly high than that of
the T-stage, N-stage, and M-stage.
Conclusions: The present study proposes a non-invasive nomogram that could aid in the differential diagnosis of
pNEN and SPT. This might help the clinicians to distinguish SPT from pNEN and choose the appropriate treatments for
the patients.
Keywords: Solid pseudopapillary tumor, Pancreatic neuroendocrine neoplasm, Nomogram
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Introduction
Pancreatic neuroendocrine neoplasm (pNEN) is rare and
it is around 10 per million in 2015, which accounts for
only 5.2% of all pancreatic neoplasms [1, 2]. In the last two
decades, in order to describe these tumors, various nomen-
clatures were used, for example insulinoma, somatostati-
noma, and gastrinoma, and until 2010 the World Health
Organization (WHO) defined these tumors as neuroendo-
crine neoplasm [3]. Based on the histopathlogy and Ki-67
index, the pNENs were divided into well-differentiated
neuroendocrine tumors (NETs) and poorly differenti-
ated neuroendocrine carcinomas (NECs) [4]. In addition,
according to the clinical manifestations, the pNENs are
Open Access
*Correspondence: weiyushan@outlook.com
1 Department of Scientific Research, First Affiliated Hospital of Dalian Medical
University, Dalian, China
Full list of author information is available at the end of the article
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Wuetal. BMC Endocrine Disorders (2022) 22:255
classified into functioning or nonfunctioning neoplasms.
Functioning pNENs are characterized with specific symp-
toms, such as Zollinger-Ellison syndrome, wihich are
caused by hormones. Nonfunctioning pNENs may also
secrate hormones, however, it cannot lead to symptoms [5].
Solid pseudopapillary tumor (SPT) is a type of neoplasm
whose incidence is lower than pNEN and it accounts for
only 0.1% of all pancreatic tumors [6]. Same to pNEN, the
nomenclature vasried in the last decades and until 1996
the WHO defined these tumors as SPTs and pathologically
classified them as rare cystic pancreatic neoplasm [7]. In
contrast to pNEN, which originates from pancreatic duct
pluripotent stem cells, SPT may be derived from pancre-
atic embryonic stem cells. e 5-year survival rate of pNEN
and SPT is 45.2% and 87.2%, respectively [2]. is suggests
that the prognosis of SPT is better than pNEN. In addition,
the management of these two types of pancreatic tumors is
different. For example, due to the excellent prognosis and
low malignant biological behavior of SPT, patients with
advanced or metastatic tumors could achieve long-term
survival and, therefore, aggressive surgical resection is a
favorable intervention for these patients [8]. However, for
pNEN, aggressive surgical resection is recommended for
selected individuals with well-differentiated tumors [9].
Based on the aforementioned difference between pNEN
and SPT, the accurate diagnosis of these two tumors is
essential. Some studies reported that pNEN gives low signal
intensity on T1-weighted imaging and SPT gives high signal
intensity [10, 11]. us, magnetic resonance imaging (MRI)
could be used to discriminate pNEN from SPT. It is note-
worthy that pNEN might give a hypo-enhancement signal
[12]. In addition, both pNEN and SPT could present calci-
fication and cystic degeneration [8]. erefore, differential
diagnosis of pNEN and SPT is challenging when the atypi-
cal characteristics are found in these two types of tumors.
Some studies prove that the clinical characteristics of pNEN
and SPT are different [2, 13]. However, as far as we know,
no study evaluated the performance of the clinicopathologi-
cal characteristics in distinguishing SPT from pNEN. We,
therefore, sought to evaluate the diagnostic performance of
clinicopathological characteristics and develop a non-inva-
sive clinical nomogram for discriminating pNEN from SPT.
Patients andmethods
Inclusion andexclusion criteria
We systematically searched the Surveillance, Epidemiol-
ogy, and End Results database. As indicates in Fig.1A,
the International Classification of Diseases for Oncology,
third edition (ICD-O-3) for tumors was used to identify
patients with pNENs (8150, 8151, 8152, 8153, 8154, 8155,
8156, 8157, 8240, 8241, 8242, 8243, 8244, 8245, 8246,
8249; N=5078) or patients with SPTs (8452; N=116).
Subsequently, we excluded cases in which the tumors
were not diagnosed by pathology (n=663), the informa-
tion on TNM stage (American Joint Committee on Can-
cer staging classification, 7th edition, n=2685), tumor size
(n=1238), surgery (n=1), lymphadenectomy (n=13), and
survival status were unclear (n=1) (Fig.1A). Totally, five
hundred and ninety-three patients, sixty seven pNEN
patients and seven SPT patients, were enrolled in the
training cohort.
Statistical analysis
e survival time of patients was presented by the
Kaplan-Meier curve, and the statistically significant was
determined by the log-rank test (Fig. 1B). To describe
the distribution of the data, the mean value and standard
deviation were used for continuous variables. If the data
followed a standard normal distribution and the vari-
ance of the two groups was equal, the statistical signifi-
cance was evaluated by the student t-test. For categorical
variables, the data were presented as the number and the
percentage of patients. e statistical significance of the
differences was determined by Fisher’s exact test or Pear-
son’s chi-squared test (Table1). To find out the variables
which could be used to discriminate pNEN from SPT,
the univariate logistic regression was performed and the
variables with P-value < 0.05 were used to perform the
multiple logistic regressions (Table2). Subsequently, the
sensitivity and specificity of age, gender, T-stage, N-stage,
and M-stage were evaluated by receiver operating char-
acteristic (ROC) curves (Fig.2). All the statistical analysis
and the graphs were performed by SPSS 19 (IBM SPSS
Statistics), and the nomogram was created by R software
using the ‘rms’ package (Fig.3A).
Results
Clinical characteristics ofpNEN andSPT
Five hundred and ninety-three patients with pNENs
and 30 patients with SPTs were enrolled in the training
cohort (Fig.1A). We observed that the overall survival of
patients with SPTs was significantly longer than that of
patients with pNENs (SPTs vs. pNENs: 140.931 ± 6.810
Fig. 1 The flowchart of patient selection and the prognosis of patients. We collected the cases from SEER databases. Finally, 563 patients with pNEN
and 30 patients with SPT were included in the present study (A). Compared to pNEN, SPT significantly increased the probability of survival (B) and
significantly decrease the hazard of death (C). SEER: Surveillance, Epidemiology, and End Results; pNEN: pancreatic neuroendocrine neoplasm; SPT:
pseudopapillary tumor
(See figure on next page.)
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Wuetal. BMC Endocrine Disorders (2022) 22:255
Fig. 1 (See legend on previous page.)
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Wuetal. BMC Endocrine Disorders (2022) 22:255
vs. 81.743 ± 3.295; P < 0.001; Fig.1B). To determine the
probability of death caused by pNENs or SPTs, the cumu-
lative hazard of death was calculated and we found that
pNENs significantly increased the hazard of death and
reduced the survival of patients (pNENs vs. SPTs: 92.239
± 3.475 vs. 140.931 ± 6.870; P < 0.001; Fig.1C). In addi-
tion, we observed that the age of patients with SPTs was
significantly younger than that of patients with pNENs
(SPTs vs. pNENs: 33.30 ± 15.15 vs. 57.40 ± 16.61; P
< 0.001) and 93.3% of the SPTs patients were female
(Table 1). Moreover, compared to SPTs, pNENs have
advanced T-stage, N-stage, and M-stage (Table1).
The performanceof clinical characteristics fordierential
diagnosisof pNENs andSPTs
To determine the clinical characteristics which could be
used to discriminate pNENs from SPTs, we performed
the univariate and multivariate logistic regression. We
observed that old age (age≥33 years), male, T-stage,
advanced N1-stage, and advanced M1-stage were the
independent risk of pNENs. To evaluate the performance
of these characteristics for differential diagnosis of pNENs
and SPTs, we performed the ROC curve and we observed
that the area under the curve (AUC) of age, gender,
T-stage, N-stage, and M-stage was 0.82 (95%CI:0.71-0.92,
P<0.05;Fig.2A), 0.75 (95%CI:0.68-0.82,P<0.05;Fig.2B),
0.65 (95%CI: 0.56-0.73, P<0.05; Fig. 2C), 0.69 (95%CI:
0.62-0.77, P<0.05;Fig.2D), and 0.70 (95%CI: 0.62-0.78,
P<0.05; Fig. 2E), respectively. is suggests that age,
gender, T-stage, N-stage, and M-stage might be valu-
able clinical characters that could be used to distinguish
pNENs from SPTs.
Development andvalidation ofanon‑invasive nomogram
forthediagnosis ofpNENs andSPTs
To integrate the aforementioned variables and establish
a non-invasive tool, which could help the clinicians with
differential diagnoses of pNENs and SPTs, we developed
a nomogram based on age and gender (Fig.3A). To inves-
tigate the performance of this non-invasive nomogram,
we performed the ROC curve (Fig.3B) and determined
the AUC of this nomogram, we observed that the AUC
of this nomogram (AUC: 0.88; 95%CI: 0.80-0.95; Fig.3C)
was significantly high than that of T-stage (AUC: 0.65;
95%CI: 0.56-0.73), N-stage (AUC: 0.69; 95%CI: 0.62-
0.77), and M-stage (AUC: 0.70; 95%CI: 0.62-0.78).
Discussion
In the present study, we observed that age, gender,
T-stage, N-stage and M-stage were valuable clinical char-
acters that could be used to distinguish pNENs from
SPTs. However, in order to obtaine the information of
T-stage, N-stage and M-stage, the tumor tissues should
be isolated from the pancrease by invasonal technolo-
gies, such as ultrasound-guided fine-needle biopsy (EUS-
FNB) or surgical resection. We, thererfore, excluded
these variabes from the present study and developed a
non-invasive nomogram by age and gender. As indicated
in Fig.3A, a female (68 points) and under the age of 33
Table 1 The clinicopathological characteristics of patients
pNEN Pancreatic neoroendocrine neoplasm, SPTs Solid pseudopapillary tumor
* Student-t test
# Fisher exact test
$ Pearson chi-squared test; AJCC American Joint Committee on Cancer
pNEN (N=563) SPT (N=30) P‑value
Age (Mean±SD, years) 57.40±16.61 33.30±15.15 < 0.001*
Gender < 0.001#
Male 315 (56.0%) 2 (6.7%)
Female 248 (44.0%) 28 (93.3%)
Race 0.403$
White 419 (74.4%) 19 (63.3%)
Black 51 (9.1%) 4 (13.3%)
Other 93 (16.5%) 7 (23.3%)
Location 0.304$
Head 160 (28.4%) 8 (26.7%)
Body/Tail 267 (47.4%) 18 (60.0%)
Other 136 (24.2%) 4 (13.3%)
Tumor Size (mm) 41.07±30.77 35.33±28.61 0.318*
T-Stage < 0.001$
T1-Stage 114 (21.3%) 2(6.7%)
T2-Stage 172 (32.1%) 21(70.0%)
T3-Stage 151(28.2%) 5(16.7%)
T4-Stage 46(8.6%) 2(6.7)
Tx-Stage 80 (14.2%) 0 (0.0%)
N-Stage < 0.001$
N0-Stage 329 (58.4%) 29 (96.7%)
N1-Stage 163 (29.0%) 1 (3.3%)
Nx-Stage 71 (12.6%) 0 (0.0%)
M-Stage < 0.001$
M0-Stage 284 (50.4%) 27 (90.0%)
M1-Stage 279 (49.6%) 3 (10.0%)
AJCC-Stage < 0.001$
I-Stage 170 (30.2%) 23 (76.7%)
II-Stage 101 (17.9%) 4 (13.3%)
III-Stage 13 (2.3%) 0 (0.0%)
IV-Stage 292 (49.6%) 3 (10.0%)
Grade 0.019$
Well differentiated 210 (37.3%) 5 (16.7%)
Moderately differentiated 75 (13.3%) 4 (13.3%)
Poorly differentiated 35 (6.2%) 0 (0.0%)
Undifferentiated 14 (2.5%) 0 (0.0%)
Unknown 229 (40.7%) 21 (70.0%)
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Wuetal. BMC Endocrine Disorders (2022) 22:255
years old (100 points) will have a score of 168 points,
which predicts the probility of SPT is 70%. is nomo-
gram might have some clinical implications. For example,
it might help the clinicians to accurately distinct pNENs
from SPTs and to determine an appropriate diagnostic or
treatment strategy for patients.
Although pNENs and SPTs are rare tumors, some
studies suggested that the incidence of these tumors
significantly increased in the last decade. us, pNENs
and SPTs received attention in the publications [8]. As
same as pNENs, SPTs patients have non-specific clinical
manifestations, for example, abdominal pain, abdominal
discomfort, and weight loss [14]. Usually, the patients
are hospitalized due to abdominal masses or accidentally
found a tumor in the pancreas. As presented in Fig.1B,
the survival of SPTs patients is significantly superior to
Table 2 Univariate and multivariate logistic regression
OR Odds ratio, AJCC American Joint Committee on Cancer
Variable Univariate Logistic Regression Multivariate Logistic Regression
OR β P‑value OR β P‑value
Age
< 33 years Reference Reference
≥33 years 0.019 ‑3.944 < 0.001 0.012 ‑4.386 < 0.001
Gender
Male Reference Reference
Female 17.782 2.878 < 0.001 14.247 2.657 0.002
Race
White Reference ---- ----
Black 1.730 0.548 0.336 ---- ----
Other 1.660 0.507 0.267 ---- ----
Location
Head Reference ---- ----
Body/ Tail 1.348 0.299 0.494 ---- ----
Tumor size
< 36 mm Reference ---- ----
≥36 mm -0.079 -0.079 0.834 ---- ----
T‑Stage
T1-Stage Reference Reference -----
T2‑Stage 6.959 1.940 0.010 28.840 3.362 0.001
T3-Stage 1.887 0.635 0.453 18.830 2.935 0.010
T4‑Stage 2.478 0.908 0.371 196.699 5.282 < 0.001
N‑Stage
N0-Stage Reference Reference
N1-Stage 0.070 ‑2.665 0.009 0.055 ‑2.902 0.012
M‑Stage
M0-Stage Reference Reference -----
M1-Stage 0.113 ‑2.179 < 0.001 0.150 ‑1.898 0.027
AJCC‑Stage
I-Stage Reference ---- ---- ----
II-Stage 0.293 ‑1.229 0.027 ---- ---- ----
III-Stage <0.001 -19.203 0.999 ---- ---- ----
IV-Stage 0.079 ‑2.532 < 0.001 ---- ---- ----
Grade
Well differentiated Reference ---- ---- ----
Moderately differentiated 2.240 0.806 0.238 ---- ---- ----
Poorly differentiated <0.001 -17.465 0.998 ---- ---- ----
Undifferentiated <0.001 -17.465 0.998 ---- ---- ----
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Wuetal. BMC Endocrine Disorders (2022) 22:255
pNENs. ese observations are supported by other stud-
ies [15, 16]. In addition, compared to pNENs, the SPTs
have relatively low malignant biological behavior. us,
aggressive surgical resection might give rise to survival
benefits in SPTs patients, even when patients with dis-
tant metastasis. Indeed, Wang et al. reported that sur-
gical resections of the primary and metastatic lesions,
as completely as possible, could give improve the prog-
nosis of SPTs patients. However, surgical resection is
contraindicated in patients with metastatic pNENs [17].
erefore, an accurate preoperative diagnosis of SPTs
and pNENs will help the clinicians to make optimal deci-
sions and chose the appropriate treatments for SPTs and
pNENs patients, respectively.As mentioned above, SPTs
and pNENs have the same clinical symptoms and signs.
In addition, the previous study reported that SPTs exhibit
neuroendocrine differentiation and in these tumor tis-
sues the author also observed chromogranin A, CA19-
9, and vimentin which are used to diagnose pNENs
[18]. is suggests that these tumor markers could not
Fig. 2 Evaluating the diagnostic performance of clinical characters. We performed the ROC curve and observed that age (A), gender (B), T-stage (C),
N-stage (D), and M-stage (E) could distinguish pNENs from SPTs. pNEN: pancreatic neuroendocrine neoplasm; SPT: pseudopapillary tumor
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Wuetal. BMC Endocrine Disorders (2022) 22:255
distinguish SPTs from pNENs. Notably, Li etal. evaluated
the clinical and immunohistochemical characteristics
of 37 SPTs, and they observed intracytoplasmic dot-like
immunoreactivity of CD99 in these tumors [19]. is
is in contrast to pNENs tumors in which the CD99 was
observed in the membrane [19]. In addition, the authors
found a loss of E-cadherin and aberrant nuclear expres-
sion of β-catenin in SPTs. us, the expression of CD99
in combination with E-cadherin and β-catenin might be
valuable combinational tumor markers for the diagnosis
of SPTs and pNENs.
Because sometimes both SPTs and pNENs have cystic
degeneration and calcification, it is difficult to distin-
guish between SPTs and pNENs by computed tomogra-
phy (CT). It is reported that MRI is a valuable strategy
for the diagnosis of pancreatic tumors. Compared to CT,
MRI could appropriately exhibit the soft-tissue charac-
teristics, theretofore MRI could be used to evaluate the
functional and metabolic of tumors. Notably, both SPTs
and cystic endocrine tumors have the same features, such
as areas of cystic change, enhancing components, and
well-defined contours [20]. Although positron emission
tomography/computed tomography (PET/CT) is widely
used in the diagnosis of malignant tumors and pancre-
atic disease, there are very few studies that evaluated the
accuracy of PET/CT in the diagnosis of SPTs [21–23].
François et al. reported that 18F-FDOPA PET/CT was
a promising approach for the diagnosis of pNENs and
SPTs. e 18F-FDOPA PET-positive/SRS-negative lesions
might be the SPTs. However, these should be verified in
a large cohort [21]. EUS-FNB might be another promis-
ing diagnostic tool for distincitng SPTs from PNENs [24,
25]. Recently, some studies reported that the diagnostic
accuracy of EUS-FNB in combination with the immuno-
histochemical staining of β-catenin or cadherin in solid
pancreatic lesions is high than 90% [26–28]. erefore,
EUS-FNB should be recommmeded as the standard of
care for differential diagnosis of pancreatic lesions.
Notably, there are some limitations to our study. is
is a retrospective study and the confounding bias might
distort the association between the variables and SPTs.
In addition, SPTs and pNENs are rare tumors. To col-
lect as many patients as possible, we used the data in
the Surveillance, Epidemiology, and End Results data-
base which encompasses approximately 28% of the USA
population. However, after a strict selection process, only
30 SPTs patients were included in the present study. In
addition, based on the pathology and Ki-67 index, the
grade of pNENs is classified into four groups: pNET
G1 (Ki-67<2%), pNET G2 (3%<Ki-67<20%), pNET G3
(Ki-67>20%) and pNEC [4]. While this WHO classifica-
tion and the Ki-67 index are not recorded in the SEER
database, and the tumore is graded according to mor-
phological description, for example, well differentiated,
moderately differentiated and poorly differentiated.
Moreover, 40.7% cases lost the information of the tumor
grade. ese limitations of SEER database might also
cause bias when interpreting the results.
Fig. 3 Development of a non-invasive nomogram and evaluating
the diagnostic performance of this nomogram. Based on the age
and gender, we developed a non-invasive nomogram (A) and the
AUC of this nomogram was significantly high than that of the T-stage,
N-stage, and M-stage (B and C). AUC: area under the curve
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Wuetal. BMC Endocrine Disorders (2022) 22:255
Conclusions
In summary, based on the age and gender of patients, we
developed a non-invasive nomogram, which could dis-
criminate SPTs and pNEN. is nomogram might help
the clinicians appropriately diagnose SPTs and pNEN
and chose the optimal strategies for these patients.
Acknowledgments
The authors are indebtedly grateful to Dr. Zeeshan Farhaj for assistance in criti-
cally revising and proofreading the manuscript.
Authors’ contributions
YW, XZ and PG contributed to the study design. LW, DS, MS, MU, HC, TZ, and YW
contributed to data collection and analysis. YW and LW contributed to statistics.
YW, LW and TL wrote the first version of the manuscript and PG and XZ revised
the manuscript. All authors approved the final version of the manuscript.
Funding
The study was supported by the National Natural Science Foundation of China
(Grant numbers: 81973646; 82104596 and 82002633); Shenzhen Science and
Technology Innovation Commission (Grant number: RCBS20200714114958333);
Guangdong Basic and Applied Basic Research Fund (Grant number:
2020A1515110083); Shenzhen Key Medical Discipline Construction Foundation
and Sanming Project of Medicine in Shenzhen (Grant number: SZSM202111002);
the (Key) Project of Department of Education of Guangdong Province (Grant
number: 2020KZDZX1170); and Science Research Foundation of Education
Department of Liaoning Province (Grant number: LJKZ0853).
Availability of data and materials
The data and material are available from the corresponding author on reason-
able request.
Declarations
Ethics approval and consent to participate
We signed the “Surveillance, Epidemiology, and End Results Program Data-Use
Agreement” following the requirement of using the SEER database (SEER
ID: 21500-NOV 2019). Surveillance, Epidemiology, and End Results Program
obtained the informed consent of patients. All methods were carried out in
accordance with the Declaration of Helsinki.
Consent for publication
This manuscript contains no individual person’s data.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Scientific Research, First Affiliated Hospital of Dalian Medical
University, Dalian, China. 2 Department of Preventive Medicine, School of Public
Health, Dalian Medical University, Dalian, China. 3 Department of General
Surgery and Institute of Precision Diagnosis and Treatment of Gastrointestinal
Tumors, Shenzhen University General Hospital and Shenzhen University Clinical
Medical Academy, Shenzhen, China. 4 Carson International Cancer Center
and Guangdong Provincial Key Laboratory of Regional Immunity and Diseases,
Shenzhen University Health Science Center, Shenzhen, China. 5 Department
of Healthcare ManagementSchool of Health management, China Medical
University, Shenyang, China.
Received: 26 April 2022 Accepted: 30 September 2022
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