Int J Clin Exp Med 2016;9(9):18068-18073
www.ijcem.com /ISSN:1940-5901/IJCEM0023960
Original Article
Prognostic analysis of primary extra-gastrointestinal
stromal tumors
Sichang Zheng*, Zhengting Wang*, Tianyu Zhang, Shurong Hu, Mengmeng Cheng, Maochen Zhang, Yun
Lin, Liwen Hong, Xiaolin Zhou, Rong Fan, Jie Zhong
Department of Gastroenterology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai
200025, China. *Equal contributors.
Received January 13, 2016; Accepted June 8, 2016; Epub September 15, 2016; Published September 30, 2016
Abstract: Objective: To analyze factors related to the prognosis of primary extra-gastrointestinal stromal tumors
(EGISTs). Methods: The pathological and clinical data of 42 patients with primary EGISTs was collected and retrospectively analyzed. The patients were hospitalized from January 2004 to December 2013 and received complete
surgical resection in Ruijin Hospital. The follow-up of postoperative patients was performed to obtain information
about recurrence. The influence of clinical and pathological factors on the disease-free survival (DFS) of patients
was analyzed. Results: Postoperative tumor recurrence was found in 24 patients during follow-up; 8 patients died of
tumor recurrence and 1 patient died of other reasons. Kaplan-Meier univariate survival analysis revealed that tumor
size, tumor mitotic count, and Ki-67 index were correlated with the DFS of patients (P=0.024, 0.001, 0.039, respectively). Cox multivariate regression analysis confirmed that tumor mitotic count was an independent prognostic factor affecting DFS post tumor surgery. Conclusions: Tumor size, tumor mitotic count, and Ki-67 index were correlated
with EGIST recurrence. Tumor mitotic count was an independent prognostic factor influencing tumor recurrence.
Keywords: Extra-gastrointestinal stromal tumors (EGIST), prognostic factor, mitotic count, Ki-67, disease-free survival (DFS)
Introduction
Materials and methods
Gastrointestinal stromal tumors (GISTs) are the
most common type of gastrointestinal mesenchymal tumors. C-Kit genetic mutation and KIT
(CD117) expression have been observed in the
majority cases of GIST [1, 2]. The prognosis of
patients with GISTs is correlated with the tumor
site, mitotic count, size, and expression of
Ki-67 [3, 4]. The observations of mesenchymal
tumors growing outside of the gastrointestinal
tract, also called extra-gastrointestinal stromal
tumors (EGISTs), have been increasingly reported in recent years; these tumors present the
morphology, immunohistochemical features,
and molecular biological characteristics, which
are similar to those of GISTs. Only a few reports
of EGISTs are available in the literature due to
its low incidence compared with other tumors.
In this retrospective study, we analyzed several
predictive factors including clinical and pathological parameters on the diseases-free survival (DFS) of 42 EGISTs patients.
Patients and data collection
We collected and retrospectively analyzed the
clinical and pathological data of 42 patients
who were hospitalized in Ruijin Hospital and
diagnosed with EGISTs via pathological procedures during surgical treatment from January
2004 to December 2013. The initial tumor originated from the omenta, retroperitoneum, mesentery or pelvic cavity has no direct connection
to the wall of the digestive tract and pelvic viscera. All pathological sections were reviewed by
two senior pathologists to achieve a clear diagnosis. The tumor was composed of spindle
cells, occasionally epithelioid cells, and CD117
positive. Tumor size was determined as the
maximum diameter of the tumor specimen
described in pathology records after surgery.
The mitotic count was determined from 200
adjacent high-power fields within the most
active area of karyomitosis, and the average
Prognotic analysis of EGIST
Table 1. Clinical and pathological factors associate with disease-free survival (DFS)
Characcteristic
Gender
Male
Female
Age (y)
≤51
>51
Tumor Site
Retroperitoneum
Pelvic cavity
Omenta
Mesentery
Tumor Size
≤10 cm
>10 cm
Ki-67 index
≤5%
>5%
Mitotic Activity
<5/50 HPF
5~10/50 HPF
>10/50 HPF
N (%)
21 (50.00%)
21 (50.00%)
20 (47.62%)
22 (52.38%)
21 (50.00%)
7 (16.67%)
8 (19.05%)
6 (14.29%)
DFS (month) P-value
0.870
42.62±6.65
50.19±9.46
0.485
52.40±9.61
38.69±6.74
0.567
35.58±6.42
33.29±6.31
44.63±8.20
58.67±17.67
0.024
55.91±7.35
37.30±7.67
0.039
53.22±6.80
37.34±8.68
<0.001
67.35±6.20
29.23±3.68
28.31±8.90
Statistical methods
SPSS22.0 was used for statistical analysis. The
clinical and pathologic features (gender, age,
tumor site, tumor size, Ki-67 index, mitotic
activity) were selected for DFS analysis.
Univariate analysis was performed with the
Kaplan-Meier method and compared by the
log-rank test. The Cox proportional hazard
model was applied to perform multivariate
regression analysis for evaluating prognostic
factors. P<0.05 indicated statistically significant difference.
Results
Immunohistochemistry
None of the 42 patients with EGISTs revealed
metastasis during preoperative examination.
As shown in Table 1, complete surgical resection was performed on all patients-21 males
and 21 females (sex ratio, 1:1). The patients
were from 24 to 73 years old (average age,
51.14±11.86 years old). Tumor size ranged
from 3 cm to 26 cm (average size, 12.93±5.98
cm), and tumor diameter was greater than 10
cm in 25 patients (59.5%). The initial tumor
developed in the retroperitoneum of 21 patients (50.0%), in the pelvic cavity of 7 patients
(16.7%), in the mesentery of 6 patients (14.3%),
and in the omenta of 8 patients (19.1%). Abdominal distension and pain were the most common clinical symptoms (26 patients, 61.9%);
other symptoms included incomplete intestinal
obstruction in 6 patients (14.3%), fatigue and
emaciation in 4 patients (9.5%), abdominal
mass in 2 patients (4.8%), a change of bowel
habits in 2 patients (4.8%), and found by health
examination in 2 patients (4.8%). As of August
31, 2015, the median of follow-up was 45
months (range, 12-105 months). Recurrence
was present in 24 out of 42 patients at a median time of 16 months (range, 6-69 months)
post-operation. A total of 9 patients died: eight
from tumor recurrence and one from cerebral
infarction at 64 months post-operation without
recurrence.
Section of 5 μm was cut from tumor tissue
which was paraffin-embedded. Monoclonal
antibody against Ki-67, clone MIB-1 (DAKO,
dilution of 1:100), was used to cover the slide
according to the standard step of Envision
methodology. The percentage of Ki-67 staining
was observed in high-power fields with 40×
object lens, 500 tumor cells at least.
DFS calculations were performed separately
based on patients’ gender, age, and tumor site.
Kaplan-Meier survival analysis demonstrated
that differences observed were not statistically
significant (P>0.05, Table 1). Differences in
DFS among groups with different tumor sizes
were statistically significant (P=0.024; Figure
1). In fact, the smaller the tumor size, the longer
17 (40.48%)
25 (59.52%)
18 (42.86%)
24 (57.14%)
14 (33.33%)
12 (28.57%)
16 (38.10%)
HPF, high-power fields.
mitotic count in 50 high-power fields (HPF) was
specified as the mitotic count for the patient.
Follow-up
Postoperative follow-up was performed via
phone consultation, outpatient service, and
hospital imaging for all the 42 patients. Postoperative survival rate, DFS, and death among
patients were calculated. DFS was defined as
the interval from the time when the tumor was
completely removed to the time of reoccurrence. For patients without tumor recurrence,
DFS was defined as the interval from the time
when the tumor was completely removed to the
time when the latest follow-up was made.
18069
Int J Clin Exp Med 2016;9(9):18068-18073
Prognotic analysis of EGIST
Figure 1. The Kaplan-Meier Survival analysis of tumor size >10 cm predict a
poorer prognosis of EGIST.
cally significant (P=0.039;
Figure 2). Here, the lower the
Ki-67 expression, the longer
the DFS. In addition, differences in DFS among groups
with different mitotic counts
were statistically significant
(P<0.01; Figure 3). It is noticed that the higher the mitotic
count, more than 5/50 HPF,
the poorer the DFS (P<0.01;
Figure 3). Cox multivariate
regression analysis demonstrated that the larger the
tumor mitotic count, the higher the risk of recurrence. This
result suggested that mitotic
count was an independent
risk factor affecting prognosis (P=0.003; Table 2). The
life table method was used
to calculate DFS among
patients in the research at
y1, y2 and y3, and values
of 81.0%±6.1%, 59.2%±8.0%,
and 47.3%±8.3% were obtained respectively.
Discussion
Figure 2. The Kaplan-Meier Survival analysis of Ki-67 Index >5% predict a
poorer prognosis of EGIST.
the DFS. Differences in DFS among groups with
different Ki-67 expressions were also statisti18070
The incidence of GISTs, the
most common gastrointestinal mesenchymal tumor, differs according to the site of
the tumor. The tumor is most
likely to be found in the stomach and small intestine, while
it is less likely to be found
in extra-gastrointestinal sites,
such as the mesentery, retroperitoneum, pelvic cavity, and
omenta [5]. The prognosis of
GIST is correlated with the
tumor site, tumor size, and
mitotic count. The larger the
tumor size or the higher the
mitotic count, the poorer the
prognosis. Moreover, the prognosis of GIST in the stomach
is the best, while the prognosis of GIST in the small intestine is relatively poor [3, 6, 7].
In recent years, GIST in the retroperitoneum,
pelvic cavity, mesentery, and omenta without
Int J Clin Exp Med 2016;9(9):18068-18073
Prognotic analysis of EGIST
performed in some studies to
explore the possibility of homology of the tumors, but
results remain inconclusive
[11, 13-16].
Figure 3. The Kaplan-Meier survival analysis of different levels of Mitotic
Activity indicates the different prognosis of EGIST. The Mitotic Activity more
than 5/50 HPF predicts a poorer prognosis of EGIST. Group A compared with
Group B, P=0.002. Group A compared with Group C, P<0.001. Group A compared with Group C, P<0.001. Group A compared with Group D, P<0.001.
There is no statistic difference between Group B and Group C, P=0.129.
Table 2. Multivariate analysis of predictive factors for recurrence
PValue
Tumor Size (cm) (≤10 vs >10)
1.502 (0.496-4.545) 0.472
Mitotic Activity (<5 vs 5~10 vs >10/50 HPF) 2.641 (1.398-4.988) 0.003
Ki-67 index (≤5% vs >5%)
0.865 (0.297-2.520) 0.790
Factors
Odds ratio (95% CI)
connection to the wall of the digestive tract,
also known as EGIST, has been increasingly
reported. The 42 cases of EGISTs included in
this study showed the histological and morphological characteristics of GIST. Positive CD117
expression was also found using immunohistochemical assay. These findings are consistent
with those from other reports, which suggest
that EGIST and GIST are homologous tumors
[8-11]. Other researchers opine that the socalled EGIST is simply the GIST growing on the
outer wall of digestive tract, then lost its contact to the outermost muscularis propria due to
external forces and other unknown reasons
[12]. Comparison of the gene mutations of c-Kit
and PDGFR between EGIST and GIST has been
18071
The ratio of male patients to
female patients was 1:1 in
this study. Previous literature
has reported that the incidence of EGIST may be higher
in female patients than in
male patents [10, 11, 17, 18].
Other literature also reports
that the median age at onset
is 50-55 years old [10], which
is similar to the findings of this
study. The incidence of EGIST
is relatively low, composing
about 10% of overall GIST
[12]. The number of patients
with EGIST included in this
study accounted for about 6%
of all patients with GIST received by Ruijin Hospital over
the same period. Meanwhile,
the preferable site of EGISTs
observed in this work was not
identical to that described in
previous reports [10, 11]. The
most common site of EGISTs
development in this study was
the retroperitoneum; this result is considered to be related to the bias of disease entity received in the surgery
department.
Tumor size, tumor site, and mitotic count are
the classical indicators used to estimate the
biological characteristics of GIST, but these
indicators may not be completely applicable to
EGIST. According to detachment theory [12]
and the current GIST risk grading system [19],
the prognosis of the omental bursa EGIST separated from the stomach is superior to that of
EGIST in other sites. However, this finding is not
consistently supported in relevant literature
[10, 11]. The results of the present study indicate that tumor site is irrelevant to the prognosis of tumor recurrence. This difference can be
explained by the fact that EGISTs are generally
larger in size than GISTs, which may cause the
tumors to contact with other viscera in the
Int J Clin Exp Med 2016;9(9):18068-18073
Prognotic analysis of EGIST
abdominal cavity more extensively. These findings imply that the effects of EGIST may not be
considered detaching from a specific site easily. In the future, the etiology and mechanism of
EGIST need to be intensively studied.
It is rather difficult to detect EGIST in its early
stage due to its relatively inaccessible anatomical location and atypical symptom. Thus, the
average size of EGIST (>10 cm) is fairly large
when it is initially detected [10, 11, 20]. The
size of the tumor is not entirely suitable for
prognosis criteria of conventional GIST. Therefore, patients were divided into two groups
based on tumor size, i.e., the >10 cm group and
the ≤10 cm group. The larger the tumor’s diameter, the shorter the DFS time (P=0.024). Cox
multivariate regression analysis demonstrated
that tumor mitotic count was an independent
risk factor of tumor recurrence (P=0.003) and
the tumor size was not an independent risk factor of prognosis (P>0.05). Some researchers
reported that EGIST prognosis was correlated
with mitotic count but not with tumor size [10,
11, 16]. Differences in the effects of tumor size
on tumor prognosis can be attributed to differences in study end point: the study end points
were DFS rate in the present study and overall
survival rate in other studies. Differences
observed in tumor prognosis may also be due
to differences in surgeon’s personal skill and
surgical procedures. Additional biases arise
from the low incidences of EGIST and from
small sample sizes among individual studies.
Ki-67, a type of nucleoprotein that has been
correlated with the transcription of ribosomal
RNA, is expressed in all phases of cell proliferation (i.e., G1, S, G2, and M) except for the cell
stationary phase (i.e., G0) [21]. Ki-67 is a marker of cell proliferation, and its expression is correlated with tumor prognosis. As a risk factor
correlated with prognosis, the nucleoprotein
has been observed in various tumors, including
malignant breast tumor, neuroendocrine tumor
and GIST [4, 22-24]. The effects of Ki-67 have
been demonstrated in a case follow-up study of
370 patients with GISTs [4]; in this work, the
higher the Ki-67 index, the poorer the prognosis. GIST, especially high-risk tumors, may be
classified into three grades based on different
Ki-67 index (i.e., <5%, 6%-8%, >8%). The present study indicated that Ki-67 index may also
be applicable to EGIST: the higher the Ki-67
18072
index, the poorer the prognosis (P=0.039). This
finding agrees with the work of Zheng [11].
Multivariate Cox regression analysis revealed
that Ki-67 index was a correlational factor
instead of an independent risk factor of prognosis. The disparity in Ki-67 results observed
between the present and other studies may
stem from differences in the pathogenesis of
GIST and EGIST. The bias introduced by the
small sample size may also contribute to the
variations found. Future studies on this topic
are needed to confirm our results.
In summary, the prognosis of EGIST was irrelevant to the age of onset, gender, and initial site
of tumor onset. The DFS rate was correlated
with tumor size, mitotic count, and Ki-67 index.
Among these factors, mitotic count was an
independent risk factor of EGIST prognosis.
Acknowledgements
This study was supported by Shanghai Jiaotong
University School of Medicine, Science and
Technology Foundation (No. 14ZJ10014) and
Shanghai Committee of Science and Technology Foundation (No. 13411950901).
Disclosure of conflict of interest
None.
Address correspondence to: Rong Fan and Jie
Zhong, Department of Gastroenterology, Ruijin
Hospital, School of Medicine, Shanghai Jiaotong
University, Shanghai 200025, China. E-mail: [email protected] (RF); [email protected]
(JZ)
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