Amr H. Sleema MD; Ihab S. Fayeka MD; Hany F. Habashyb MD;Amany Saberc MD;Alfred E. Namourd MD;Nevine F. Habashye MD a: Surgical Oncology Department – National Cancer Institute – Cairo University – Egypt. b: Surgery Department – Fayoum teaching hospital – Fayoum University – Egypt. c: Medical Oncology Department – Minia Cancer Center – Egypt. d: Medical Oncology Department – National Cancer Institute – Cairo University – Egypt. e: Surgical Pathology Department - National Cancer Institute – Cairo University – Egypt. Kasr el-aini journal of surgery Volume 15, No.2, May 2014

1. 1
Gastrointestinal Stromal Tumors: A
clinicopathologic study of 67 cases.
Amr H. Sleema
MD; Ihab S. Fayeka
MD; Hany F. Habashyb
MD;Amany Saberc
MD;Alfred E. Namourd
MD;Nevine F. Habashye
MD
a: Surgical Oncology Department – National Cancer Institute – Cairo University –
Egypt.
b: Surgery Department – Fayoum teaching hospital – Fayoum University – Egypt.
c: Medical Oncology Department – Minia Cancer Center – Egypt.
d: Medical Oncology Department – National Cancer Institute – Cairo University –
Egypt.
e: Surgical Pathology Department - National Cancer Institute – Cairo University –
Egypt.
Abstract
Aim: Is to study the clinicopathologic aspects of Gastrointestinal Stromal
Tumors (GISTs) with correlation between surgical resection, pathological
characterestics; disease free survival (DFS) and overall survival (OS) for
all cases in a combined retrospective and prospective study.
Patient and methods: A retrospective study for 33 patients with GISTs
at the National Cancer Institute , Minia Oncology Center and Fayoum
Teaching hospital between January 2001- December 2006 and a
prospective study for 34 patients at the National Cancer Institute , Minia
oncology center and Fayoum Teaching hospital between January 2007 -
January 2011. All patients were evaluated pre-operatively and underwent
exploratory laparotomy with surgical resection for curative intent; they
were followed up for a period ranging from 24 to 60 Months.
Results: Among the 67 patients, there were 25 males and 42 females;
77.61% of patients were above 40 years. Abdominal pain (40.3%),
abdominal mass (38.8%) and GIT bleeding (34.8 %) were the main
presentations. The stomach was the most common site of origin of the
disease (49.3%) followed by small intestine (28.4%). Tumors were high

2. 2
grade in (70.1%) and low grade in (29.9%). Complete resection of all
gross disease was accomplished in 53 patients (79.1%) and residual
disease in 14 patients (20.9%).Overall survival and disease free survival
were statistically significant in relation to the size of the tumor, the grade
of the tumor, and the resection status.
Conclusion:Complete surgical resection, including en block resection
of locally advanced tumors, remains the only curative treatment for
GISTs. The overall survival and disease free survival were significantly
affected by size of the tumor, grade of the tumor and the resection status.
Keywords
Gastrointestinal stromal tumor – Sarcoma - CD117 - CD34 – Imatinib -
surgical resection.
Introduction
Gastrointestinal stromal tumors (GISTs) are the most common
mesenchymal tumors of the gastrointestinal tract (1). They account for
1% of all GI tumors. Their origin was at first attributed to interstitial cells
of Cajal, in mesodermal tissue but it has nowadays been recognized that
GISTs arise from multipotential mesenchymal stem cells (2). GISTs are
defined as pleomorphic mesenchymal tumors of the GI tract that express
the KIT protein (CD117-Protooncogene that encodes the transmembrane
tyrosine kinase receptor CD117 and in some gastrointestinal stromal
tumors often also CD34 on immunohistochemistry (3). GISTs
demonstrate a fairly equal distribution between men and woman although
some literature suggests that GIST has a slight male predominance (4).
Although GIST has been documented in patients of all ages, most of the
people affected by GIST are between 40 and 80 years old at the time of

3. 3
diagnosis with the median age of 60 years (5).The proportion of overtly
malignant or high-risk GISTs is considered to be 20-45% of all GISTs
(6), which suggests that the annual incidence of GISTs with a high
malignancy potential is about 5 - 6.8 per million (7). GISTs present as
well circumscribed, highly vascular tumors in the wall of subserosa of the
gastrointestinal tract. On gross examination, these tumors appear fleshy,
pink or tan-white, and may show hemorrhage. Large tumors frequently
show cystic degeneration or necrosis even in the absence of prior
treatment (8). Most GlSTs (60% to 70%) arise in the stomach, 20% to
30% originate in the small intestine, and less than 10% in the esophagus,
colon, and rectum. GISTs can also occur in extra intestinal sites in the
abdomen or pelvis such as the omentum, mesentery or retroperitoneum
(9). The vast majority of studies on GISTs suggest that the two most
important prognostic features to assess the risk of aggressive behavior in
a primary GIST are mitotic activity and tumor size. These two features
were the foundation of the consensus approach for risk assessment in
GISTs (10). According to the new guidelines (11) GISTs smaller than 2
cm without significant mitotic activity (<5 per 50 high-power fields) can
be regarded as essentially benign. The next strongest parameter in these
studies was tumor location, small intestinal and rectal GlSTs were more
aggressive than gastric GlSTs of similar size (12). The clinical
presentation of GIST varies widely, approximately 70% of patients with
GIST were symptomatic, 20% were asymptomatic, and 10% were
detected at autopsy. GISTs that caused symptoms tended to be larger with
an average size of 6 cm. versus 2 cm. for asymptomatic GISTs and 1.5
cm. for GISTs detected at autopsy (13). Total surgical resection still
constitutes the standard treatment for non-metastatic GISTs, since it is the
only modality of treatment capable of being curative. The complete R0
resection (absence of residual disease) represents one of the most

4. 4
important determinant factors in the treatment outcome (disease-free
interval and survival); RO resection is achieved in approximately 40% to
60% of all cases of GIST and in over 70% of the non-metastatic case
(14). The primary goal of surgery is the total resection of the tumor. The
type of resection to be performed is dependent on tumor location and
size. Lesions suspected of having invaded adjacent organs must be treated
by radical surgery through an en bloc resection of the organs involved. It
is mandatory that the resection achieves negative margins verified by
intraoperative frozen section examination, since the presence of residual
disease negatively influences survival (15). The presence of lymph node
metastasis has not been recognized as a prognostic factor (16); in fact, no
data can be found in the literature to support routine lymphadenectomy.
Therefore, lymphadenectomy should be performed when gross
examination suggests lymph node involvement.
For patients presenting with metastatic or recurrent GIST, the exact place
of surgery in the Imatinib era remains to be determined. Surgery is
generally not indicated if a patient presents with generalized disease
progression under treatment. In such situation, the outcomes appear to be
marginal: one study reported no patients free of recurrence at 12 months
(17) and another reported a median time to progression of 3 months (18).
The aim of this study is to correlate the clinicopathologic aspects of
Gastrointestinal Stromal Tumors (GISTs) with surgical resection,
pathological characterestics; disease free survival (DFS) and overall
survival (OS) for all cases in a combined retrospective and prospective
study.
Patient and methods
A retrospective study of 33 patients (January 2001- December 2006), and

5. 5
a prospective study of 34 patients (January 2007 - January 2011) at the
National Cancer Institute, Minia Oncology Center and Fayoum Teaching
Hospital.
All patients were evaluated pre-operatively with complete laboratory
investigations, chest radiograph and CT abdomen and pelvis with oral
and IV contrast. Upper and lower GIT endoscopies were performed when
indicated while an endoscopic biopsy done when the later was feasible.
All patients underwent exploratory laparotomy aiming at complete
surgical resection with a curative intent; they were followed up for
periods ranging between 24 – 60 Months.
All specimens were examined in relation to the risk factors, namely size,
and histopathological grade and safety margin "R status". All specimens
were also subjected to immunohistochemistry staining including CD34
cent CD117, tumors exhibiting mitotic rate 5/50 per high-power field
(HPF) or less were defined as low grade and those exhibiting mitotic rate
> 5/50 HPF as high grade tumors.
Results
Among the 67 patients in the studied population female predominance
was obvious where 25 patients were men (37.3%) and 42 patients were
women (62.7%). The median age was 49.7 years. 15 patients (22.4%)
were under age of 40, 27 patients (40.3%) in the range between 40 and 60
years and 25 patients (37.3%) were above 60 concluding that 77.6% of
the patients were above 40 years old.
All patients were symptomatic on presentation, the most common
symptom was pain in 27 patients (40.3%),other clinical manifestations
included palpable mass in 24 patients (35.8%), GIT bleeding in 22

6. 6
patients (32.8%), Nausea & vomiting in 8 patients (11.9%), Anemia in 17
patients (25.4%) weight loss in 6 patients (9%) and constipation in 5
patients (7.5%).
Computed tomography (CT) of the abdomen and pelvis was the most
commonly used investigation (Figures 1 and 2), being done for 65
patients (97.6%). The other investigations used included upper GI
endoscopy in 17 patients (25%) and lower GI endoscopy used in 11
patients (16.4%).
Endoscopic abnormalities were demonstrated in 14 of 17 patients who
underwent upper GIT endoscopy (82.3%). Those abnormalities were:
extra gastric mass in 10 patients (71%) and ulcerative mass in 4 patients
(29%).As for lower GIT endoscopy, abnormalities were detected in 9 of
the 12 patients in whom it was performed (75%), Detected abnormalities
were: ulcerating and extra luminal mass in 7 patients (77.7%) and 2
patients (22.2%) respectively. FNAC was done in 8 patients only and was
positive diagnosis only in 6 of 8 patients.
Anatomic distribution of the tumors is listed in (Table 1). The most
common site of origin was the stomach (Figure 3) 33 patients (49.3%),
followed by the small intestine (Figure 4 & 5) 19 patients (28.4%), the
colon and rectum 9 patients (13.4%), Mesentery 5 patients (7.5%) and
least frequently abdominal wall 1 patient (1.5%).
Postoperative pathology revealed tumor size more than 5 cm. in 56
patients (83.6%) and less than 5 cm. in 11 patients (16.4%). Tumors
exhibited high histopathologic grade in 47 patients (70.1%) and low
Grade in 20 patients (29.9%). Microscopic examination revealed spindle
cell appearance in 55 patients (82.1%), epithelioid in 5 patients (7.5%)
and mixed in 7 patients (10.4%). Receptor status was studied in most of
cases, CD117 was positive (Figure 7) in 28 cases (41.8 %) and negative
in 12 cases (17.9%), CD34 was positive in 25 cases (37.3%) and negative

7. 7
in 10 cases (14.9%). Actin was done in 20 cases (29.9%) and Desmin in 5
cases (7.5%) all of them were negative (Table 2). The incidence of lymph
node involvement in our series was 0%.
The different operative procedures (Figure 6) performed during this
study are listed in (Table 3). Complete resection with final negative
pathologic margins (R0) was accomplished in 53patients (79.1%) and
incomplete resection either microscopic (R1) or gross (R2) was
documented in 14 patients (20.9%).
Intra-operatively 3 complications (4.4%) were reported in the form of 2
minor bladder injuries (2.9%) due to extensive adhesions and repaired
primarily in 2 layers and a single case (14.9%) of major vascular injury
(aorta) which was repaired. Post-operatively 4 morbidities and 2
mortalities, two cases with wound sepsis, one cysto-cutaneous urinary
fistula, and the fourth patient suffered from malnutrition all cases were
managed conservatively.
Disease free survival (DFS) was calculated from the date of primary
tumor resection to the date of recurrence or the last follow-up date. DFS
and Overall survival (OS) were assessed in relation to the following
variables: size of the tumor (Table 4), grade of the tumor (Table 5) and
completeness of resection (Table 6). Statistical analysis revealed a better
DFS and OS with tumors <5 cm. in diameter, low grade and completely
resected tumors. Cases with tumor size 5 < cm (11 cases) had disease free
survival 45.63+13.46 and overall survival 46.18+12.32 while tumors >
5cm (56 cases) had DFS 25.96+13.29 OS 27.46+11.99. And this
difference was statistically significant (P-Value > 001). Twenty patients
had low-grade tumors whose DFS was 43.55+8.49 and OS 43.95+7.83
while 47 patients had high-grade tumors with a DFS 23.08+13.05 and OS
24.82+11.75 (P-Value < 001). DFS was 33.35+ 13.93 and OS

8. 8
33.77+13.46 in tumors completely resected, while tumors incompletely
resected or with positive margins DFS was 13.42+6.79 and OS
18.28+6.61 (P value <001).
In the prospectively studied 34 patients only 16 patients (47.1%) received
adjuvant therapy 14 patients of them received Imatinib myselate and 2
patients received other chemotherapeutic regimens due to the high cost
and unavailability of Imatinib myselate.
Discussion
GIST represents the most common mesenchymal tumor of the gastro-
intestinal tract, a female predominance in this study representing 62.7%
of patients, however a fairly equal distribution between men and woman
in the literature (19). About 77.6% of patients in our study were above 40
years with a median age of 49.7 years. In comparison to Kim KM et al.
2005, who reported over 90% of GISTs occur in adults over 40 years,
with a median age of 63 years (5).
The symptoms associated with primary gastro-intestinal stromal tumors
are usually vague and nonspecific which is a contributing factor in the
delayed diagnosis associated with GIST (20). Despite the fact that most
patients in our study were symptomatic either with pain, abdominal mass
and/or GIT bleeding .Previous studies report that only 70% of patients are
symptomatic, while 20% are asymptomatic and 10% detected in autopsy
(21). This was explained by the large size of tumors in this study in
comparison to the small size (< 2 cm) of asymptomatic tumors in others
(22).
By analysis of the utility of the frequently ordered diagnostic studies that

9. 9
were performed before surgical exploration, the most frequently ordered
diagnostic test in our series was the CT scan (97.1%) which demonstrated
the mass, determined its size and its relation to contiguous organs and it
confirmed the presence or absence of distant metastases. A primary tumor
is typically a well- circumscribed and often highly vascular mass closely
associated with stomach or intestine .GISTs usually appear heterogeneous
due to necrosis or intramural hemorrhage. Upper GIT endoscopy to
evaluate a patient with upper gastrointestinal bleeding seems a reasonable
first test to detect a benign source but it was our general impression that
these studies added little in terms of planning the extent and the type of
the operation because most of the endoscopically detected lesions were
extra-luminal with an intact mucosa. Needle biopsy was performed
infrequently and, when performed, was not helpful in the establishment of
a definitive diagnosis. No other imaging tests (including upper
gastrointestinal contrast study or abdominal ultrasound scanning) were
found to be more sensitive than CT for the detection and staging of a
primary GIST.
In this study, tumors originated most frequently from the stomach 49.3%,
these finding are similar to other reports in which the stomach was
involved in 38% to 65% of cases (4, 23, 24). The small intestine was the
second most common site of origin representing 28.4% correlating with
other reports in which the small intestine represents about 30% of tumor
origin (4).
Regarding the size of the primary GISTs in this study, 83.6% of patients
had tumors greater than 5 cm and 16.4% had tumors less than 5 cm. This
was explained by the latent period between the start of disease and
initiation of symptoms and delay for seeking a medical advice. Small
tumors (< 5 cm.) had a significantly better DFS and OS. Similarly,

10. 10
several studies demonstrated that tumor size more than 5 cm significantly
affect survival (24) where the 5 –years DFS rate for patients with primary
tumor < 5 cm was 95% (52.1-100) ,5-10 cm 31.2% (16.6-42.8) and > 10
cm 22.5% (11.5-33.6).
As with sarcomas elsewhere, histological grade is a powerful prognostic
characteristic. Previous Reports have shown that low grade lesions are
associated with improved overall 5-year survival in the 40% to 80%
range compared with high-grade lesions with overall survival rates
between 16% and 28% (25), and this correlates with our study where
significant better DFS and OS were detected in low grade tumors.
In the current study, Spindle cell tumors represented 82.1% of all cases,
epithelioid cell type 7.5 % and Mixed type 10.5 % which are close to
percentages to many studies (26), however Miettinen et al 2006 stated
that spindle cell GISTs represent approximately 70%, epithelioid GISTs
20% and mixed spindle and epithelioid cyto-morphology approximately
10% (8).
Characteristically stain positively for CD117 and CD34, but less
commonly for Actin and Desmin which are expressed typically by
leiomyosarcoma and shwanomas, respectively (20). In our study, about
79% of patients were positive for CD117 and CD34 Compared to other
studies which reported positive CD 117 in 85-94% (27) and positive
CD34 in 52-72% of cases (28).
Complete surgical resection emerged as the most important prognostic
variable in this study. Complete resection were achieved in 79.1% of
patients and residual disease either microscopic or gross were in 20.9%;
similarly Jason S et al 2006 achieved complete resection in 80% of cases

11. 11
(29). In a recent report, Langer et al., 2003 reported the outcome of 39
patients following surgery. Complete (R0) resection was achieved in 35
of 39 patients and from whom only five died from recurrent disease,
compared with 3 of 4 patients with involved margins (30). Incomplete
resection should only be performed for palliation of pain, bleeding or
symptoms due to mass effect.
Univariate analysis of different studies of GIST found that tumor size of
less than 5cm, low histological grade, presence of localized disease, and
complete surgical resection without tumor spillage were all favor-able
prognostic factors (31).
The incidence of lymph node involvement in our series was 0%, which is
consistent with a low incidence of lymph node metastases seen in other
reports (less than 2%) (32).
In conclusion complete resection with an aggressive attempt to remove all
gross disease and achieve negative margins remains the fundamental
surgical principle in the management of GIST. Extensive preoperative
testing and biopsy do little and not recommended; still CT is the best
modality for evaluation of GIST. For localized gastric tumors, wedge
resection with negative margins appears adequate. More extensive gastric
lesions may require total gastrectomy or en bloc resection of adjacent
organs. Small bowel and colon lesions are removed with segmental
resections and, when indicated, may require the removal of involved
contiguous organs. As the incidence of lymph node involvement is low,
extended lymph node dissections are not warranted.

12. 12
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16. 16
Figure (1): CT abdomen axial cut for gastric GIST
Figure (2): CT abdomen sagittal cut for jejunal GIST
Figure (3): Small exophytic gastric GIST from the anterior wall of the stomach.

17. 17
Figure (4): Small jejunal GIST.
Figure (5): A large lobulated Jejunal GIST

18. 18
Figure (6): Sleeve resection of the stomach using GIA-90 stapler.
Figure (7): C Kit + ve Slides

19. 19
Table (1): Anatomic distribution of GISTs
Origin: Frequency (N=67) Percentage
Stomach.
Small intestine.
Colon / rectum.
Mesentery.
Abdominal wall.
33
19
9
4
1
49.3
28.4
13.4
6
1.5
Table (2): Receptors' Status
Receptors
+ve -ve
Frequency Percent Frequency Percent
CD117.
CD34.
Actin.
Desmin.
28
25
0
0
41.8
37.3
0
0
12
10
20
5
17.9
14.9
29.9
7.5

20. 20
Table (3): operative procedures
Type of operation. Frequency
(N=67)
Percentage
Sleeve Gastrectomy. 15 22.4
Partial Gastrectomy. 9 13.4
Partial Gastrectomy + omentectomy. 1 1.5
Partial Gastrectomy + omentectomy +
splenectomy.
2 3
Partial Gastrectomy + splenectomy + distal
pancreatectomy.
2 3
Partial Gastrectomy + splenectomy +
segmental colonic resection.
1 1.5
En block resection of mesenteric mass. 4 6
Extended RT. hemicolectomy. 3 4.5
LT. Hemicolectomy. 1 1.5
Sigmoid colectomy. 2 3
Abdomino-Perineal Resection 1 1.5
Partial Gastrectomy + splenectomy. 2 3
Total Gastrectomy + subtotal colectomy +
splenectomy + omentectomy.
1 1.5
Small intestine resection anastomosis. 15 22.4
Intra-abdominal abscess drainage + resection
of jejunal mass.
1 1.5

21. 21
Right hemicolectomy. 2 3
Transverse colectomy. 1 1.5
Cystic mass excision + pancreatectomy. 1 1.5
Huge mass excision + partial cystectomy. 1 1.5
Excision of mass of abdominal wall +
prolene mesh
1 1.5
Mesenteric mass en block resection with
transverse colectomy.
1 1.5
Table (4): Effect of size on DFS and OS
Less than 5 cm More than 5 cm P value
Disease free
survival
45.63 ± 13.46 25.96 ± 13.29 <0.001
Overall survival 46.18 ± 12.32 27.46 ± 11.99 <0.001
Table (5): Effect of tumor grade on DFS and OS
Low grade High grade P value
Disease free
survival
43.55 ± 8.49 23.08 ± 13.05 <0.001
Overall survival 43.95 ± 7.83 24.82 ± 11.75 <0.001

22. 22
Table (6): Effect of completeness of resection on DFS and OS
R0 R1&2 P value
Disease free
survival
33.35 ± 13.93 13.42 ± 6.79 <0.001
Overall survival 33.77 ± 13.46 18.28 ± 6.61 <0.001