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37]

Review Article

Diagnosis and management of

gastrointestinal stromal tumors: An
up‑to‑date literature review
ABSTRACT Ayman
Gastrointestinal stromal tumors (GISTs) are rare life‑threatening forms of cancer that may arise anywhere in the GI tract. Herein, we El‑Menyar1,2,
aimed to review the literature to describe the incidence, management, and outcomes of GISTs. We conducted a traditional narrative Ahammed
review using PubMed and EMBASE, searching for English‑language publications for GISTs between January 2001 and January Mekkodathil1,
2016 using keywords ““gastrointestinal” “stromal tumors.” Among 4582 retrieved articles, 50 articles were relevant over the last Hassan Al‑Thani3
15 years. Several risk stratification systems exist to predict the outcomes of GISTs based on certain criteria such as the primary 1
Department of
site of occurrence, size of the tumor, mitotic activity, staining for proliferating cells, and tumor necrosis. Risk stratification is crucial Surgery, Clinical
in the management and outcomes of the disease. Surgical resection remains the gold standard option of GISTs treatment. Complete Research, Trauma
resection of the tumor is the main predictor of the postoperative patient’s survival. Laparoscopic resections are associated with less Surgery, Hamad
intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, laparoscopy General Hospital,
2
Department of
is difficult to perform in large and unfavorably placed GISTs and may result in disease progression, recurrence, and poor survival. Clinical Medicine,
Robot‑assisted laparoscopic resections provide instruments for surgeons to perform technically demanding operations. Moreover, Weill Cornell Medical
extensive research work including large clinical trials is ongoing to establish promising role of the adjuvant and neo-adjuvant therapy College, 3Department
for better disease- free survival in GIST patients. of Surgery, Hamad
General Hospital,
Doha, Qatar
KEY WORDS: Gastrointestinal, stromal, tumors
For correspondence:
Prof. Ayman
El‑Menyar,
INTRODUCTION in males in some studies; the male to female ratio Clinical Research,
Trauma Surgery,
in incidence ranged from 1.02 to 1.7.[2,5,9‑12] Herein,
Hamad General
Gastrointestinal stromal tumors (GISTs) are rare life we aim to review the literature to describe the Hospital,
threatening forms of cancer representing 0.1–3% of incidence, management, and outcomes of GISTs. P.O. Box 3050,
all the GI malignancies. Moreover, GISTs account for Doha, Qatar.
80% of the GI mesenchymal neoplasms.[1] The major E‑mail: aymanco65@
LITERATURE SEARCH STRATEGY yahoo.com
cause of GIST is the presence of an abnormal form
of tyrosine protein kinase (KIT) protein also known A traditional narrative literature search was
as CD117, which causes uncontrollable growth of performed using the PubMed and EMBASE search
the GI cells. Population‑based studies have shown engines. The search was limited to the duration
that the annual incidence of GISTs is 11–20 per
from January 2001 to January 2016. We used the
million population.[2,3] GISTs may arise anywhere
search terms in different combinations to enhance
in the GI tract and are recognized as originating
the retrieval of articles. In addition, Google Scholar
from gut pacemaker cells known as interstitial
searches were also carried out. Reference lists of
cells of Cajal (ICC) or their stem cell precursors
that are distributed along the GI tract from the appropriate studies were also hand‑searched to
esophagus to the anus.[4] Although it can appear include further studies for potential inclusion.
Access this article online
at any age, advanced age is a risk factor for GISTs A total of 4582 articles were retrieved from Website: www.cancerjournal.net
and the median age of onset reported in previous DOI: 10.4103/0973-1482.177499
This is an open access article distributed under the terms of the Creative Commons
studies was about 60 years.[5‑7] The incidence of Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix,
PMID: ***

GISTs is much less in individuals below the age of tweak, and build upon the work non‑commercially, as long as the author is credited Quick Response Code:

40 and GISTs are very rare in children and young and the new creations are licensed under the identical terms.
adults.[8] A slightly higher incidence rate was seen For reprints contact: reprints@medknow.com

Cite this article as: El-Menyar A, Mekkodathil A, Al-Thani H. Diagnosis and management of gastrointestinal stromal tumors:
An up-to-date literature review. J Can Res Ther 2017;13:889-900.

© 2017 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow 889
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El‑Menyar, et al.: Gastrointestinal stromal tumors
different search engines. We excluded videos, errata, letters,
and corrections. Finally, 50 articles were deemed suitable for
inclusion in the review after the exclusion of 4532 articles not
relevant to the current review. Two relevant papers included
from the reference lists were not within the limit of the
duration in our search strategy.
Of 50 articles included, 23 were retrospective studies,
22 were prospective studies, two were case reports, two were
meta‑analyses, and one was randomized controlled trial.
The sample size in retrospective population‑based studies
ranged from 22 to 6998 GIST patients whereas it was 5–2537
in prospective studies. Table 1 shows sample size, type, year
of publication, and origin of studies included in this review.
TRENDS IN INCIDENCE AND SURVIVAL OF GASTROINTESTINAL
STROMAL TUMORS
GISTs are associated with a broad spectrum clinical behavior.
Many patients are usually asymptomatic and incidentally
found to have GIST during imaging or exploration.[1] Metastatic
GISTs often progress rapidly which account for 15–50% of
cases.[1] Nearly 70–90% of the GISTs are caused by c‑KIT somatic
gain‑of‑function mutations followed by similar mutations in
platelet‑derived growth factor receptor‑alpha (PDGFRA).[13]
PDGFRA gain‑of‑function mutations account for approximately
half of c‑KIT‑negative GISTs.[13] Both c‑KIT and PDGFRA genes
are located in the fourth chromosome in humans which
encodes tyrosine kinase receptors. The risk of GIST increases
with the inheritance of the mutations and, in some instances,
GISTs can be found in several members of the same family.
Furthermore, GISTs being a part of genetic syndrome possibly
linked with other syndromes such as neurofibromatosis type 1
and carney triad.[14]
GISTs were frequently misclassified as GI autonomic nerve
tumor, leiomyoma, leiomyoblastoma, leiomyosarcoma, or
schwannoma.[15] However, a proper classification of GIST was
established in 2002 based on the fact that KIT mutations are
the major causes of GISTs. Over the years, advancements in
immunohistochemical staining techniques, improvements in
diagnosis, and improved registration led to increase in the
incidence of GIST as reported in various population‑based
studies.[9]
For example, a 25‑fold increase in the rate of incidence was
noted in the USA in 10 years since 1992.[16] Similarly, the
nationwide study in the Netherlands showed the annual
incidence of GIST increased 6‑fold in 8 years since 1995 whereas
the incidence of GIST‑like tumors decreased by 28%; however,
the GIST incidence rate was stable from 2000 onward.[17]
In Japan, GISTs were registered in 1988 for the first time
and found increased since 1999 whereas leiomyosarcomas
have decreased.[10] Nomura et al. concluded that GIST might
have been diagnosed as leiomyosarcoma before using
immunohistochemistry.
890 Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
The trend in GIST survival rate was also found increased over the
years, especially after the year 2000. Perez et al. attributed the
increase in GIST survival rate found in the USA after 2000 to
the launch of imatinib mesylate (imatinib), a KIT‑selective
tyrosine kinase inhibitor (TKI).[16] The Taiwanese nationwide
cancer registry‑based study in 2986 GIST patients pointed
out that the widespread use of imatinib resulted in better
outcomes.[9] The study showed that 5‑year overall survival (OS)
increased from 58.9% (1998–2001) to 70.2% (2005–2008).[9] A
recent trend analysis based on over 5000 GIST patients from
the surveillance, epidemiology, and end results (SEER) registry
revealed an increase in OS from 15% in 1998 to 55% in 2008
in metastatic GIST.[18] However, the Spanish population‑based
study between 1994 and 2001 showed a favorable survival
in preimatinib population.[19] This improved survival in
preimatinib era could be due to misclassification of very
low‑risk GIST as leiomyoma.[18] Metastatic or recurrent GISTs
are often associated with poor survival; however, patient
outcomes improved significantly with the advent of imatinib
and other KIT‑selective TKIs.[1,18]
SITES OF OCCURRENCE AND CLINICAL PRESENTATION
A population‑based study in Western Sweden showed
that 21% of GISTs were discovered incidentally during
surgery for unrelated conditions including surgery for other
intra‑abdominal malignancies such as colorectal carcinoma or
gastric carcinoma, and 10% were detected during autopsies.[20]
Kawanowa et al. revealed that most of the incidentally found
tumors were microscopic GISTs and many of them were located
in the stomach.[21] Nearly 85% of the benign incidental tumors
showed KIT mutations which were similar to the clinically
significant GIST case series with larger size, suggested that
KIT mutations occur very early in the GIST development.[22]
Many studies revealed that GISTs arise more commonly in the
stomach (40–70%) followed by the small intestine (15–44%) and
rarely seen in intra‑abdominal sites (2–11%) such as omentum,
mesentery, and retroperitoneum.[5,8,11,12,19] Extra‑GISTs may also
present in organs such as liver, pancreas, prostate, ovaries, and
uterus. Its occurrence was reported as nearly 10% in a Chinese
survey.[5] It has been reported that metastatic GISTs frequently
occur at liver (65%) and peritoneum (21%).[8]
GIST associated symptoms vary with the site and size of the
lesion. Small‑sized GISTs often do not have any symptoms.
Increase in size may develop mass‑related symptoms such
as abdominal pain, digestive discomfort, and sensations of
fullness of the abdomen. Caterino et al. studied the correlation
between symptoms, location, and prognosis and reported
that nearly 38% of the GIST patients were presented with
epigastric or periumbilical abdominal pain.[23] GISTs were
located mainly (3 of 5) in the stomach. The most frequently
noted clinical manifestation for GISTs was GI bleeding that
resulted from mucosal ulceration which occurs in nearly half
of the GIST cases.[24,25] GI bleeding may change the texture of
the stool to either dark‑red or black. In addition, bleeding leads
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El‑Menyar, et al.: Gastrointestinal stromal tumors

Table 1: Studies included in the review

Authors Year Sample Study type Country Conclusion
size
Ducimetière et al.[2] 2011 748 Population‑based France The observed incidence of sarcomas was higher than expected
(retrospective)
Mazzola et al.[3] 2008 Population‑based Switzerland Higher age‑standardized rates compared to other European
(retrospective) countries. The gene mutation spectrum differed when compared to
the literature
Wang et al.[5] 2013 153 Population‑based China Low incidence of GIST, no statistically significant difference exists
(retrospective) in the incidence between males and females
Yan et al.[6] 2008 22 Population‑based Canada There was a trend for increased GIST incidence with routine use
(retrospective) of CD117
Mucciarini et al.[7] 2007 124 Population‑based Italy GIST incidence comparable to other European countries. Survival
(retrospective) was favorable in lower risk categories and in most of the resected
cases
Rubió et al.[19] 2007 46 Population‑based Spain GIST incidence rate was low, survival was favorable in preimatinib
(retrospective) population, but was low in high‑risk cases
Nilsson et al.[20] 2005 1460 Population‑based Sweden GIST has been under‑recognized: Its incidence, prevalence, and
(retrospective) clinical aggressiveness also have been underestimated
Tryggvason et al.[51] 2005 57 Population‑based Iceland GIST incidence data supports the NIH consensus prognostic
(retrospective) categories
Goettsch et al.[17] 2005 Population‑based The Netherlands The increased GIST incidence related to increased understanding
(retrospective) of GIST pathobiology and the routine availability of the diagnostic
immunohistochemical antibody directed against the CD117 antigen
Chiang et al.[9] 2014 2986 Population‑based Taiwan GIST incidence increased, partially due to the advancement of
(retrospective) diagnostic techniques and increased awareness by physicians.
The outcome has improved significantly with imatinib
Nomura et al.[10] 2013 6998 Population‑based Japan GIST might have been diagnosed as leiomyosarcoma in digestive
(retrospective) organs before using immunohistochemistry
Bokhary and 2010 37 Population‑based Saudi Arabia GISTs prevalence more than expected, with most in male adults
Al‑Maghrabi[11] (retrospective) over 40 years of age. Gastric GISTs were frequent. Most tumors
belong to high‑risk group
Barakat et al.[12] 2010 93 Population‑based Jordan A slight male predominance for high‑risk GISTs
(retrospective)
Perez et al.[16] 2006 Population‑based USA GIST incidence increased since 1992. Survivals have greatly
(retrospective) improved since 2000, when imatinib mesylate was FDA approved
Kawanowa et al.[21] 2006 100 Prospective Japan Microscopic gastric GISTs are common and only few may grow
into a clinical size with malignant potential
Corless et al.[22] 2002 120 Prospective USA KIT mutation activation is acquired in the early stage of the
development of most GISTs and is of little prognostic importance
Caterino et al.[23] 2011 47 Prospective Italy Symptoms correlate to tumor location, to class risk criteria as
mitotic index and risk classifications
DeMatteo et al.[24] 2000 200 Prospective USA Disease‑specific survival tumor size can be predicted in patients
with primary disease undergoing complete gross resection
Sorour et al.[25] 2014 92 Prospective Egypt GIST‑related emergencies are increasing. Early diagnosis and
treatment are crucial in saving lives. Surgery is the gold standard
treatment in localized GIST. Prognosis is strictly related to size and
completeness of surgical resection
Emory et al.[34] 1999 1004 Prospective USA Tumor location, size, mitotic index, and age have independent
value in predicting the prognosis of patients with gastrointestinal
smooth‑muscle tumors
Wu et al.[35] 2003 57 Prospective USA Imatinib‑targeted therapy of metastatic disease yields encouraging
clinical responses
Pierie et al.[36] 2001 70 Retrospective USA Tumors having more than 1 mitosis and larger than 5 cm in size
associated with poor prognosis, with decreased survival, and
increased local and/or distant recurrence
Cao et al.[37] 2010 181 Retrospective China Surgical resection is the gold standard. NIH risk stratification is
simple and effective to evaluate GIST behavior and prognosis.
Imatinib therapy may play an important role in the treatment of GIST
Dematteo et al.[38] 2008 127 Prospective USA Recurrence in completely resected primary GIST is independently
predicted by mitotic rate, tumor size, and tumor location in the
absence of tyrosine kinase inhibitor therapy
Emile et al.[40] 2004 276 Retrospective France KIT or PDGFRA mutations were detected in 58.4% of the
c‑KIT‑positive and also in some c‑KIT‑negative tumors
Martín et al.[41] 2005 162 Prospective Spain Deletions affecting codons 557 to 558 are relevant for the
prognosis of RFS in GIST patients
Bachet et al.[42] 2009 68 Retrospective France KIT exon 11 mutations were correlated with the origin of GIST, but
not with prognosis or response to imatinib

Contd...

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El‑Menyar, et al.: Gastrointestinal stromal tumors

Table 1: Contd...
Authors Year Sample Study type Country Conclusion
size
Andersson et al.[43] 2006 177 Prospective Sweden KIT exon 11 deletion is an independent adverse prognostic factor
in patients with GIST
Cho et al.[44] 2006 56 Prospective Japan KIT mutations, especially deletions in exon 11, are markers of poor
prognosis for gastric GISTs
Antonescu et al.[45] 2004 24 Prospective USA GISTs have heterogeneous gene expression depending on KIT
genotype and tumor location
Nakamura et al.[52] 2005 80 Prospective Japan results strongly support the hypothesis that Ki‑67 LI and risk grade
are useful for predicting the aggressive biologic behavior of GISTs
Rutkowski et al.[53] 2007 335 Retrospective Poland Primary tumor location and sex are independent prognostic factors
of GIST
Takahashi et al.[54] 2007 303 Retrospective Japan Fletcher’s system could be enhanced by the addition of “clinically
malignant factors” and “clinically malignant group” could be
potential candidates for adjuvant therapy using imatinib
Miettinen et al.[57] 2005 1765 Prospective USA Molecular genetic study showed patients with point mutations
related to better outcomes than those with deletions
Goh et al.[58] 2008 171 Retrospective Singapore Remarkable prognostic heterogeneity exists in the AFIP high‑risk
category. Study suggests a new system that provides the most
accurate prognostic information
Sanchez Hidalgo 2010 52 Prospective Spain The Fletcher risk scores have the greatest sensitivity and
et al.[59] specificity to predict overall survival, and recurrence compared
with other scores
Gold et al.[60] 2009 127 Prospective USA The proposed nomogram accurately predicts RFS after resection
of localized primary GIST and could be used to select patients for
adjuvant imatinib therapy
Woodall et al.[61] 2009 2537 Prospective USA Tumor size, grade and the presence of metastases did affect
overall survival. When combined in a TGM staging system, grade
and metastasis were the factors most predictive of survival
Karakousis et al.[65] 2011 155 Prospective USA Laparoscopic resection of primary gastric GISTs≤8 cm results
in shorter hospital stays with similar operating room time while
showing sound oncologic outcomes compared with open resection
when matched for tumor size
Liang et al.[66] 2013 776 Meta‑analysis China The laparoscopy might be superior to open surgeries for the
patients with GIST<5 cm
Koh et al.[67] 2013 765 Systematic Singapore Laparoscopic resections result in superior short‑term postoperative
review and outcomes without compromising oncological safety and long‑term
meta‑analysis oncological outcomes compared with open resections
Buchs et al.[68] 2010 5 Prospective Switzerland Robotic system offers oncologically safe resection for an
unfavorably located gastric GIST. Moreover, the three‑dimensional,
high‑definition vision, instrument mobility, and ease of performing
a difficult suturing enable a safe, large atypical gastrectomy, close
to the pylorus or cardia
Desiderio et al.[69] 2013 5 Prospective Italy Robotic surgical resection of large GISTs is feasible and
associated with favorable outcomes
Ortiz‑Oshiro 2012 1 Case report Spain Robotic surgical resection is technically feasible and safe because
et al.[71] of the advantageous movements provided by the robotic arms
Moriyama et al.[72] 2012 1 Case report Japan Robot‑assisted laparoscopic resection for gastric GIST is a safe
and feasible technique. The da Vinci Surgical System simplifies
resecting and suturing the stomach with an appropriate margin
Song et al.[74] 2009 100 Retrospective South Korea Robot‑assisted gastrectomy with lymphadenectomy can be applied
safely and effectively for patients with gastric cancer
Patriti et al.[75] 2008 13 Prospective Italy Robot‑assisted laparoscopic lymph node dissection and
esophageal anastomosis are feasible and safe
Blanke et al.[77] 2008 147 Prospective USA Nearly half of patients with advanced GIST who were treated with
imatinib mesylate survived for more than 5 years, regardless the
starting dose
Dematteo et al.[78] 2009 713 Randomized, USA Adjuvant imatinib therapy is safe and seems to improve
double‑blind, RFS compared with placebo after the resection of primary
placebo‑controlled gastrointestinal stromal tumor
trial
Al‑Thani et al.[80] 2014 48 Retrospective Qatar A total of 48 GIST patients were identified. Surgical resection
analysis was the preferred choice of treatment; however, robotic and
laparoscopic resections were feasible and safe
RFS=Recurrence‑free survival, GIST=Gastrointestinal stromal tumor, TGM=Tumor‑grade‑metastasis, AFIP=Armed Forces Institute of Pathology, PDGFRA=Platelet‑
derived growth factor receptor‑alpha, NIH=National Institutes of Health, FDA=Food and Drug Administration

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El‑Menyar, et al.: Gastrointestinal stromal tumors
to occasional vomiting of blood. Chronic bleeding may lead to
anemia which causes fatigue and in some cases tachycardia.
Caterino et al. showed GI bleeding (58%) and abdominal
pain (61%) were more frequent in gastric GISTs; however,
other acute abdominal symptoms were more common in
jejunal (40%) and ileal GISTs (60%).[23]
Although it was not statistically significant, gastric GISTs
showed abdominal pain as the main symptom was larger
in size compared to gastric GISTs with bleeding as main
symptom. Similarly, acute abdominal symptoms, which include
appendicitis‑like pain, GI obstruction, or tumor rupture, were
frequent with larger jejunal/ileal GISTs.[22] Acute abdomen
symptoms require emergency medical attention. GIST rupture
was very rare in previous reports. However, rupture and
peritonitis were noted in 8% of GIST patients in GIST‑related
emergency study by Sorour et al.[25]
DIAGNOSIS AND IMMUNOHISTOCHEMISTRY
Radiological examinations may not provide useful data on
localization of GISTs. It can be achieved by the use of barium
contrast studies, endoscopy, and computed tomography (CT)
scan. CT scan also helps in determining size and presence
of secondary localizations such as hepatic metastases.
Positron emission tomography may be useful for secondary
localization. However, histological and immunohistochemical
confirmation are required.[26] Immunohistologic features
of GISTs differentiate it from other mesenchymal tumors
such as leiomyomas, schwannomas, leiomyoblastomas, and
leiomyosarcomas.[27] Immunohistochemically, GISTs and ICC
are KIT‑positive, suggesting GISTs arise from ICC. However,
GIST arises from the locations where ICC are absent such as
mesentery or omentum suggests the origin of GISTs are from
stem cell precursors of ICC.[28]
Other important markers used in the diagnosis of GISTs include
CD34, vimentin, keratin, smooth muscle actin (SMA), and S100.
They are usually positive for vimentin and may be positive for
SMA and keratin but often negative for desmin and protein
S100.[26] The National Comprehensive Cancer Network (NCCN)
reported the proportion of positivity of GISTs toward various
markers as KIT (95%), CD34 (60–70%), SMA (40%), S‑100 (5%),
desmin (1–2%), and keratin (1–2%).[29]
Other markers currently explored include protein kinase
C-theta and carbonic anhydrase II (CAII), nestin, and Discovered
on GIST-1 (DOG1).[30] DOG1, also known as TMEM16A and ANO,
is a promising biomarker with high sensitivity and specificity.
Wong reported that one‑thirds of KIT‑negative GISTs were
positive for the antibody DOG1.[30] According to Lee et al., DOG1
antibodies are more sensitive than KIT in detecting gastric
GISTs, tumors with epithelioid morphology, and tumors with
PDGFRA mutation.[31] Moreover, DOG1 immunoreactivity is
virtually absent in other mesenchymal and nonmesenchymal
tumor types and its use in combination with KIT will be
Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
beneficial in identifying the patients for targeted therapies.
However, the role of DOG1 is uncertain especially when
KIT and PDGFRA mutation analysis by polymerase chain
reaction and gene sequencing of tumor biopsy specimens is
available.[32] Kakkar et al. recently studied the utility of DOG1
immunocytochemistry and reported DOG1 immunopositivity
in 57% of the cases examined.[33] The authors concluded that
DOG1 immunocytochemistry can serve as a valuable adjunct
in ambiguous cases.[33]
PROGNOSTIC FACTORS
Variations in aggressiveness of GISTs are evident in the
published literature. Studies have shown the occurrences of
GISTs ranging from small benign nodules to malignant tumors
in all sites. Many criteria exist to predict the biological behavior
of GISTs, which include the primary site of occurrence, size
of the tumor, mitotic activity, staining for proliferating cells,
and tumor necrosis.
Emory et al. demonstrated the significant difference in
site‑specific survival for 10 years in 1004 GIST patients.[34]
The authors argued tumor size and mitotic activity alone was
not sufficient to predict the long‑term outcomes in any sites.
Moreover, mitotic activity was found highly site dependent.
For similar mitotic figures and size in 50 high‑power
fields (HPFs), gastric GISTs had shown better survival when
compared to small bowel GISTs.[35] Demetri et al. reported
esophagus has the best prognosis whereas peritoneum has
the worst.[29]
DeMatteo et al. analyzed the outcomes of 200 patients with
GISTs and predicted the survival by tumor size in patients with
primary disease after complete resection of gross disease.[24]
Recurrence was predominantly intra‑abdominal and noted
in the original tumor site, peritoneum, and liver. Wu et al.
showed that GIST size larger than 5 cm along with other factors
predicted recurrence in patients after surgical treatment.[35]
Pierie et al. showed that GISTs with size more than 5 cm
contributes to decrease in survival.[36] Cao et al. confirmed that
large tumor size is associated with worse prognosis in GIST
patients undergoing surgical resection.[37]
In addition, studies have concluded that a mitotic rate >5/10
HPFs is a predictive of the aggressive behavior of cells.[34,35]
Mitotic rate is a measure of tumor cell proliferation indicating
the rate of growth of the tumor. Mitotic index can be
considered as the most important single variable in prognosis
of GIST.[38] In short, tumor size, mitotic index, and tumor origin
site are the important variables widely accepted in predicting
the biological behavior of GISTs.
Other prognostic criteria include tumor necrosis, staining for
proliferating cells (MIB‑1 >10%), invasive character, presence
of symptoms, and evidence of metastases, or lymph node
invasion.[26]
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El‑Menyar, et al.: Gastrointestinal stromal tumors
A recent study by Kargin et al. assessed the relationship
of raised blood neutrophil-to- lymphocyte ratio with the
prognosis in GIST patients.[39] The authors found that this
ratio significantly increased in the high‑risk patients and was
associated with short survival.[39] Further, an increase in this
ratio was associated with an increase in the mitotic activity
of the tumor.[39]
GENE EXPRESSION AND AGGRESSIVE BEHAVIOR
Studies identified that 60% of gain‑of‑function mutations
occurs within the exon 11 of KIT which consists of 33 codons
(codons‑550‑582). Deletions involving amino acids W557
and/or K558 (delWK) are more common (8–25% of KIT exon
11 mutations) which in fact are associated with higher rate of
recurrence.[38,40,41] Contrarily, Emile et al. found GISTs in which
the last part of exon 11 (codons 562–579) frequently deleted
and was associated with malignancy compared to GISTs with
deletion of the first part (codons 550–561).[40] However, several
studies have shown that deletions at distal part of exon 11,
particularly Tyr568 and/or Tyr570 (delTyr), are less common
compared to delWK which accounts for 3–8% of exon 11
mutations.[38] Bachet et al. showed that GISTs with delTyr and
delWK mutations had similar prognosis after surgical resection
and targeted therapy with imatinib.[42] Mutations involving
duplication or substitutions at KIT exon 11 showed better
prognosis when compared to KIT exon 11 deletions.[38,43,44]
Similarly, KIT exon 9 mutations had unfavorable outcomes.[38]
Evidence suggests that tumor site of origin is associated
with mutations. Often, GISTs with KIT exon 9 mutations were
located in the small intestine and with PDGFRA mutations
in stomach.[45] However, significant association between KIT
exon 11 mutation status and tumor site of origin was not
established.[46,47] Bachet et al. analyzed a large series of patients
and showed that GISTs with delWK were mainly gastric and
with delTyr were mainly intestinal.[42] Since both deletions
lead to similar worse prognosis according to Bachet et al.,
the researchers concluded that gastric and small bowel GISTs
are associated with same poor prognosis.[42] However, Corless
et al. argued that KIT mutation activation is acquired in the
early stage of the development of most GISTs and are of little
prognostic importance.[22]
GISTs may show other gene abnormalities such as telomerase
expression. Loss of expression of some genes may result in
aggressive behavior. Sun et al. argued telomerase RNA can
repress GIST growth which may be mediated by inhibition of
telomerase activity and downregulation of Bcl‑2 expression.[48]
RISK STRATIFICATION SYSTEMS
National Institutes of Health consensus criteria (Fletcher’s
criteria)
Malignant potential of GISTs varies ranging from small benign
lesions to fatal sarcomas. GIST grading for malignant potential
894 Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
in the pre‑KIT era was based on tumor size, mitotic count, and
proliferative index and classified GISTs into low and high risks.
The old grading system considered GISTs and true smooth
muscle neoplasms together as stromal neoplasms.[49]
Risk stratification system has been further modified with
the advent of KIT. The National Institutes of Health (NIH)
consensus criteria, also known as Fletcher’s criteria, was
developed in the year 2002.[50] Eight prognostic categories
based on tumor size (≤2, >2–5, >5–10, and >10 cm) and
mitotic activity (<5 vs. >5/50 HPFs) with four subdivisions
of risk groups such as very low, low, intermediate, and high
risk were followed to assess the malignant potential. Mitotic
rate used in this system is an alternative to proliferative index
followed in the old grading system. A size of 5 cm was fixed
as the cut‑off value to define low and nonlow risk tumors.[49,50]
Prediction of recurrence or metastasis based on the tumor
size and mitotic rate that followed in NIH system was verified
by several studies. Swedish, Icelandic, and Japanese studies
showed high proportion of recurrences in patients classified as
high‑risk group according to NIH criteria. It was noted as 63%,
41%, and 39%, respectively.[20,51,52] A slight male predominance
in high‑risk cases was evident in Jordanian population.[12] In the
Swedish study, none of the patients classified as very low‑risk
group had recurrent tumor disease or tumor‑related deaths.[20]
In addition, the low‑ and intermediate‑risk groups showed low
proportion of tumor recurrence, i.e., 2.4% and 2%, respectively.
Mortality associated with tumor collectively in very low‑,
low‑, and intermediate‑risk groups was shown as only 1.2%.
Intermediate‑risk groups showed a higher recurrence of
20% in Iceland‑based study suggesting intermediate risk
along with high‑risk influences negatively on the survival
rate.[51] However, the recurrence proportion in these groups
was lower in Japanese study which recorded as 4.5%.[52]
Iceland‑based study concluded that the positive predictive
value for aggressive behavior of the high‑risk category was
46% whereas the negative predictive value of both low and
very low risk was 100%.[51]
Revised National Institutes of Health criteria
Modification of the NIH risk system was proposed by several
authors and suggested inclusion of other prognostic factors.
Although Rutkowski et al. validated the NIH system, they
suggested addition of independent prognostic factors
such as primary tumor location and sex.[53] Notably, several
studies showed the general tendency for the NIH system
to overgrade gastric tumors and downgrade a subset of
nongastric tumors when compared to other systems based
on the tumor site of origin which developed later. Rutkowski
et al. also showed that nonradical resection (R1) and tumor
rupture were associated with adverse outcome.[53] Takahashi
et al. found “clinically malignant” factors such as peritoneal
dissemination, metastasis, invasion, and tumor rupture
affected disease‑free survival and, therefore, suggested
the modification of NIH system with addition of “clinically
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El‑Menyar, et al.: Gastrointestinal stromal tumors
malignant” group to include patients presenting any of
these factors.[54]
However, the revised NIH criteria was based on Joensuu’s
proposal for modification based on two facts such as
(1) nongastric tumors have high risk of recurrence compared
to gastric GISTs of the same size and mitotic count and
(2) tumor rupture contributes to the increased risk. [55]
Joensuu suggested the inclusion of patients with certain
nongastric tumors (2.1–5 cm + >5 mitoses per 50 HPF or
5.1–10 cm + ≤5/50 HPF) and cases with tumor rupture in
the NIH high‑risk category. As mentioned earlier, several
authors were in favor of prognosis based on anatomical
sites. Moreover, tumor rupture was identified as a factor
which negatively influences the survival. If the revised NIH
system is applied, the disease recurrence in high‑risk group
category will increase by 15–20% and the positive predictive
value for the aggressive behavior of high‑risk category
increases as well.[55]
Armed Forces Institute of Pathology criteria (Miettinen’s
criteria)
Unlike Fletcher’s criteria, Armed Forces Institute of Pathology
(AFIP) criteria, known as Miettinen’s criteria, considers the
anatomic site of the tumor and included the risk group of
“benign tumors” with no risk of malignancy.[56,57] Miettinen’s
criteria was based on large series with nearly 1900 GIST
cases having different sites of origin and with long‑term
follow‑up. According to these criteria, gastric GISTs ≤10 cm
and ≤5 mitoses per 50 HPFs possess a low risk for metastasis
whereas >5 per 50 HPFs and >5 cm in diameter have a
high‑risk for metastasis. On the other hand, all intestinal
GISTs >5 cm regardless mitotic rate have at least moderate
risk for metastases and all >5 mitoses per 50 HPFs have a
high‑risk for metastases. Intestinal GISTs  ≤5  cm with  ≤5
mitoses per 50 HPFs has a low risk for metastases. Notably,
nongastric tumors represented nearly 90% of all tumors which
metastasized in the Icelandic population‑based GIST study.[51]
The positive sides of Mietttinen’s criteria over NIH system
are that NIH system was based on expert opinions whereas
Miettinen system was based on study data in around
1900 GIST patients and a long‑term follow‑up based on
tumor location, size, and mitotic rate. Goh et al. compared
Miettinen’s criteria with NIH criteria and confirmed the
superiority of Miettinen’s criteria in predicting the patient
outcomes.[58] The researchers observed that patients with
mitotic counts >5/50 HPFs and tumor size 5–10 cm had
fewer recurrences compared to tumor size >10 cm which
resulted in a suggestion of modification of AFIP system with
addition of “very high‑risk” group with tumor size >10 cm
and mitotic count >5/50 HPFs.[58]
The major shortfall of Miettinen’s criteria is the complexity
of the system by having excessive prognostic subgroups,
which might reduce the prognostic sensitivity and specificity
Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
of recurrence. The total area used for mitotic count varied
in different studies; however, AFIP suggested an area of
5 mm2. Counting remains as an issue when irregular‑shaped
lymphocytes and other inflammatory cells between tumor cells
and presence of apoptotic bodies in GIST are considered.[49,59]
Memorial Sloan‑Kettering Cancer Center nomogram
In 2009, Gold et al. (Memorial Sloan‑Kettering Cancer Center
sarcoma team) developed a nomogram to predict recurrence‑free
survival (RFS) after surgery in GIST patients.[60] The risk of
tumor progression was estimated using a point system based
on tumor site (gastric, small intestine, colon/rectum, extra‑GI),
size, and mitotic activity. The probabilities of RFS at 2 and
5 years were predicted by the nomogram and calculated as
100% minus the predicted probability of RFS.
The Surveillance, Epidemiology, and End Results‑based
tumor‑grade‑metastasis system
Woodall et al., based on SEER, proposed a system for GIST
staging based on a tumor‑grade‑metastasis (TGM) system.[61]
The system follows a cut‑off point for tumor size 70 mm in
defining clinical behavior in GISTs in place of tumor sizes
(2, 5, and 10 cm) used in previous risk stratification systems.
The presence of nodal and distant metastasis was regarded
as advanced stage in this system. Tumor size (T1, ≤70 mm;
T2, >70 mm; P < 0.001), grade (G1, Grades I and II;
G2, Grades III and IV; P < 0.001), and presence of metastases
(M0, no; M1, yes; P < 0.001) affected OS. Grade and metastasis
were the factors most predictive of survival when combined
in a TGM staging system.[61]
American Joint Committee on Cancer staging for
gastrointestinal stromal tumor
In 2010, Edge and Compton, on behalf of the American
Joint Committee on Cancer, introduced a staging system for
GISTs, by adopting the Miettinen’s criteria and incorporating
tumor (T) node (N) metastasis (M) status.[62] In addition, a
grade category was assigned to tumors based on mitotic
rate. A “low grade” was assigned for 5 or fewer mitoses per
50 HPF and “high grade” for 6 or more mitoses per 50 HPF.
The most remarkable aspect of TNM classification is the
subdivisions of high‑risk category into substages (II, IIIA, or
1MB). However, further studies are required to validate this
subclassification.
SURGICAL TREATMENT
Currently, surgical resection remains as the gold standard
in the treatment for GISTs. The clinical practice guideline
by European Society for Medical Oncology considers every
GIST as potentially malignant and recommends surgical
management of all GISTs without metastasis.[63] Resectability
depends on the tumor dimension and localization. [61]
Complete removal (R0) of the tumor and the surrounding
tissue is the goal of the surgery as completeness was found
related to postoperative survival in patients with GISTs
895
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El‑Menyar, et al.: Gastrointestinal stromal tumors
localized to primary organ sites.[24] Surgical resections were
indicated even if it was incomplete, aimed at palliation of
symptoms related to mass effect and the risk of bleeding.
Unresectable GISTs should undergo molecularly targeted
intervention with imatinib mesylate, and complementary
resection should be considered if GISTs responds to the
medication. [26] In patients with primary GISTs, surgical
resection offers a 5‑year survival rate of 48–70%.[24,34,35]
Studies revealed the prognosis of low‑risk GIST after complete
resection was excellent while high risk has a high rate of
recurrence.[26] Unresectable patients normally have short
survival and frequent recurrence. Sorour et al. showed that
median survival among unresectable GIST patients was
nearly12 months.[25]
Surgical management of gastrointestinal stromal tumors
including open surgeries, laparoscopic method, and robot
assisted surgeries are the commonly used methods in the
resection of GISTs.[64-68] Laparoscopic resections had shown
advantages over traditional open surgeries. Postoperative
pains, infections, hernia, dehiscence associated with longer
incisions in traditional open resections are less likely to occur
in laparoscopic resections. In addition, laparoscopy provides
clear view of intraoperative field and helps in minimizing
the damage caused by hands and instruments during the
procedure, enhances postoperative recovery, and results in
short hospital stay. Furthermore, diagnosis and treatment of
GISTs can be done while performing laparoscopic resection.[65]
Karakousis et al. demonstrated that laparoscopic resection of
primary gastric GISTs ≤8 cm resulted in shorter hospital stays
and associated with better oncologic outcomes compared with
open resection.[65]
A recent meta‑analysis on laparoscopic versus open gastric
resections for gastric GISTs, which included 17 studies
involving 776 participants showed laparoscopic resections
were associated with favorable outcomes such as less
intraoperative blood loss, early return of bowel function,
early resumption of diet, and short hospital stay. However,
there were no differences in terms of recurrence, operative
time, and overall complications.[66] Laparoscopic resection
was shown as a strategy with higher overall success (93%)
compared with open surgeries (88%) by the decision analysis.
Koh et al. also confirmed that laparoscopic resections result
in better short‑term postoperative outcomes and long‑term
outcomes without compromising oncological safety compared
with open resections.[67]
However, the two‑dimensional visualization, counterintuitive
instrument movement, limited instrument mobility, and
surgeon fatigue due to abdominal wall torque limit the use
of conventional laparoscopic equipment. Therefore, the use of
the laparoscopic technique in large and unfavorably located
GISTs is limited. The NCCN restricts the use of laparoscopy
for tumors <2 cm in dimension.[29] In unfavorably placed
GISTs, instrument mobility is affected and suturing becomes
896 Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
difficult while performing laparoscopic resection. It can also
result in inadequate resection margins or tumor spillage and
consequently end in disease progression, recurrence, and poor
survival.[69]
Robot‑assisted laparoscopic resections are in place to address
the shortfalls with laparoscopic resections by providing
instruments for surgeons to perform technically demanding
operations.[68-70] It may be advantageous in surgical resection of
large and unfavorably located GISTs, especially placed at pylorus
or cardia. Da Vinci surgical system offers superior ergonomics,
enhanced vision, precision, dexterity, and control for surgeons
to operate.[70-71] The three‑dimensional high definition images
can be magnified up to 10 times so that surgeons have a close
view of the operating area. The mechanical wrists that bend
and rotate resemble the movements of the human wrist and,
therefore, allow surgeons to make small and precise movements.
In addition, the software incorporated with da Vinci minimizes
the effects of a surgeon’s hand tremors on instrument
movements.[70] Recent studies also found that the minimally
invasive robotic resection was oncologically safe and resulted
in favorable outcomes such as earlier return of bowel function,
earlier resumption of diet, decreased duration of the use of
analgesia, and shorter postoperative hospitalization.[68,69,71,72]
Hashizume and Sugimachi in 2003 reported the first
robot‑assisted gastrectomy in10 patients in South Korea.[73]
Since then, it was proven safe and feasible by many researchers
particularly in lymph node dissection for gastric cancer
and adenocarcinoma.[74,75] Song et al. series was the largest
in this regard which comprised 100 patients with gastric
adenocarcinoma. [74] However, only a few studies were
published regarding the use of da Vinci system in oncologic
resection for gastric GISTs. Buchs et al. performed esogastric or
duodenogastric junction preservation in five GIST cases located
at cardia or antrum and found oncologically safe resection was
possible with the robotic system.[68] Similarly, Desiderio et al.
series of five GIST cases underwent robotic gastric resection of
tumors located at unfavorable positions, i.e., cardia or antrum.[69]
TARGETED THERAPY WITH IMATINIB
Identification of the fact that oncogenic mutations in tyrosine
kinases such as KIT or PDGFRA stimulated the growth of
the cancer cells resulted in the development of TKIs such as
imatinib aimed at inhibition of tumor proliferation. The US
Food and Drug Administration granted accelerated approval
for the use of imatinib for patients with advanced or metastatic
GIST in 2002. In 2008, the approval included patients at an
increased risk for recurrence after surgical removal of the
GIST and regular approval was granted for patients with
metastatic GIST.[76]
Wu et al. studied imatinib‑targeted therapy in the treatment of
GIST and showed that use of drug in metastatic disease yields
promising clinical responses.[35] Blanke et al. showed the improved
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El‑Menyar, et al.: Gastrointestinal stromal tumors

survival of patients with advanced GISTs with imatinib treatment Table 2: Clinical trials for gastrointestinal stromal tumor cancer
and reported that median survival increased approximately from Tyrosine kinase inhibitors of KIT and/or PDGFRA
20 to 60 months.[77] This study among 147 patients showed that Nilotinib (brand name Tasigna)
Sorafenib (brand name Nexavar)
nearly half of patients with advanced GIST, when treated with Pazopanib (brand name Votrient)
imatinib mesylate, survived for more than 5 years, regardless of Dasatinib (brand name Sprycel)
starting dose. Wu et al. reported disease stabilization or tumor Masitinib (AB1010)
regression in 39% of patients in a median duration of response Regorafenib
Crenolanib (CP‑868,596)
of 19 months, in their study.[35] Taiwanese population‑based study OSI‑930
noted the OS in preimatinib period (1998–2001) and imatinib Cediranib (AZD2171)
period (2005–2008) and found the significant improvement with Amuvatinib (MP470)
Dovitinib (TKI258)
the use of imatinib as OS increased from 58.9% (preimatinib) to DCC‑2618: Trial expected to open
70.2% (imatinib).[9] Perez et al. showed the marked improvement Biologic inhibitors of KIT or PDGFRA
in GIST survival in the US since 2000 paralleled the introduction Olaratumab (IMC‑3G3)
of imatinib into clinical practice.[16] Cell cycle inhibitors
Vorinostat (brand name Zolinza)
Ixabepilone (brand name Ixempra)
The effectiveness experienced in unresectable GISTs led their CUDC101
use in both preoperative and adjuvant therapy. Preoperative Panobinostat
Insulin‑like growth factor pathway inhibitors
treatment with imatinib improves the resectability by reducing
BIIB022
the size of the tumors (neoadjuvant therapy) which were AMG 479
initially inoperable. This was found safe, reducing surgical MK0646
morbidity lowers the risk of bleeding and ruptures and may Figitumumab (CP‑751,871)
Linsitinib (OSI‑906)
reduce the extent of the operation.[32] The drug was also XL228
indicated after complete resection of primary GIST with higher Cixutumumab (IMC‑A12)
risk of recurrence as adjuvant therapy (preventive). Takahashi MEDI‑573
et al. suggested the use of imatinib as an adjuvant therapy in HSP90 inhibitors
Ganetespib STA‑9090
patients with peritoneal dissemination, metastasis, invasion, Retaspimycin (IPI‑504)
or tumor rupture where the disease‑free survival is largely Tanespimycin (17‑AAG, KOS‑953)
affected.[54] A phase 3 trial in patients with moderate to high SNX‑5422
AUY922
risk of recurrence, adjuvant imatinib therapy significantly AT13387
improved RFS at 1 year; however, there was no difference Inhibitors of pathways downstream of KIT and PDGFRA
in OS.[78] However, adjuvant therapy was highly benefited in RAS/RAF/MEK/ERK/MAPK inhibitors
high‑risk GISTs classified according to the AFIP risk score or XL281
RDEA119
revised NIH criteria. Based on various trials and treatment GDC‑0973 (XL518)
recommendations, Yip et al. concluded that imatinib adjuvant Selumetinib (AZD6244)
therapy is indicated in high‑risk patients for the duration of BAY86‑9766
Akt inhibitors
3 years.[79] Al‑Thani et al. described all the GIST cases in a small Perifosine
country from the Middle East, in which imatinib was found XL418
in one case only.[80] This patient showed a 10‑cm lesion with mTOR inhibitors
an intermediate risk received adjuvant imatinib therapy and Everolimus (RAD001)
Sirolimus (brand name Rapamune)
showed a favorable long‑term outcome. Temsirolimus (brand name Torisel)
Deforolimus AP23573
Clinical trials for GIST cancer are summarized in Table 2.[81] PF‑04691502
PI3K inhibitors
BEZ235
CONCLUSION SF1126
XL147
Although GIST is not common, it represents the majority of XL765 (also inhibits mTOR)
PX-866
the GI mesenchymal neoplasms. Risk stratification is crucial GDC-0941 bismesylate
in the management and outcomes of the disease. Surgical GDC-0980 (also inhibits mTOR)
resection remains as the gold standard in the treatment. PF-04691502
Complete resection is related to the postoperative survival BAY80-6946
BYL719
in patients. Laparoscopic resections are associated with less Buparlisib (BKM120)
intraoperative blood loss, early return of bowel function, MAPK=Mitogen activated protein kinase, PDGFRA=Platelet‑derived growth
early resumption of diet, and short hospital stay. However, factor receptor‑alpha
laparoscopy is difficult to perform in large and unfavorably
placed GISTs and may result in disease progression, resections provide instruments for surgeons to perform
recurrence, and poor survival. Robot‑assisted laparoscopic technically demanding operations. Moreover, extensive
Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017 897
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El‑Menyar, et al.: Gastrointestinal stromal tumors
research work including large clinical trials is ongoing to
establish promising role of the adjuvant and neo-adjuvant
therapy for better disease- free survival in GIST patients
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Raut CP, Morgan JA, Ashley SW. Current issues in gastrointestinal
stromal tumors: Incidence, molecular biology, and contemporary
treatment of localized and advanced disease. Curr Opin Gastroenterol
2007;23:149‑58.
2. Ducimetière F, Lurkin A, Ranchère‑Vince D, Decouvelaere AV, Péoc’h M,
Istier L, et al. Incidence of sarcoma histotypes and molecular subtypes
in a prospective epidemiological study with central pathology review
and molecular testing. PLoS One 2011;6:e20294.
3. Mazzola P, Spitale A, Banfi S, Mazzucchelli L, Frattini M, Bordoni A.
Epidemiology and molecular biology of gastrointestinal stromal
tumors (GISTs): A population‑based study in the South of Switzerland,
1999‑2005. Histol Histopathol 2008;23:1379‑86.
4. Min KW, Leabu M. Interstitial cells of Cajal (ICC) and gastrointestinal
stromal tumor (GIST): Facts, speculations, and myths. J Cell Mol Med
2006;10:995‑1013.
5. Wang ZH, Liang XB, Wang Y, Ma GL, Qu YQ, Tian XW. Epidemiology
survey of gastrointestinal stromal tumor in Shanxi Province in 2011.
Zhonghua Yi Xue Za Zhi 2013;93:2541‑4.
6. Yan BM, Kaplan GG, Urbanski S, Nash CL, Beck PL. Epidemiology of
gastrointestinal stromal tumors in a defined Canadian Health Region:
A population‑based study. Int J Surg Pathol 2008;16:241‑50.
7. Mucciarini C, Rossi G, Bertolini F, Valli R, Cirilli C, Rashid I, et al.
Incidence and clinicopathologic features of gastrointestinal stromal
tumors. A population‑based study. BMC Cancer 2007;7:230.
8. Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria
of gastrointestinal stromal tumors (GISTs): A review. Eur J Cancer
2002;38 Suppl 5:S39‑51.
9. Chiang NJ, Chen LT, Tsai CR, Chang JS. The epidemiology of
gastrointestinal stromal tumors in Taiwan, 1998‑2008: A nation‑wide
cancer registry‑based study. BMC Cancer 2014;14:102.
10. Nomura E, Ioka A, Tsukuma H. Incidence of soft tissue sarcoma
focusing on gastrointestinal stromal sarcoma in Osaka, Japan, during
1978‑2007. Jpn J Clin Oncol 2013;43:841‑5.
11. Bokhary RY, Al‑Maghrabi JA. Gastrointestinal stromal tumors in
Western Saudi Arabia. Saudi Med J 2010;31:437‑41.
12. Barakat FH, Haddad HA, Matalka II, Al‑Orjani MS, Al‑Masri MM,
Sughayer MA. Characteristics of gastrointestinal stromal tumors in
a Middle Eastern population. Saudi Med J 2010;31:797‑802.
13. Hirota S, Isozaki K. Pathology of gastrointestinal stromal tumors.
Pathol Int 2006;56:1‑9.
14. Agarwal R, Robson M. Inherited predisposition to gastrointestinal
stromal tumor. Hematol Oncol Clin North Am 2009;23:1‑13, vii.
15. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs):
Definition, occurrence, pathology, differential diagnosis and
molecular genetics. Pol J Pathol 2003;54:3‑24.
16. Perez EA, Livingstone AS, Franceschi D, Rocha‑Lima C, Lee DJ,
Hodgson N, et al. Current incidence and outcomes of gastrointestinal
mesenchymal tumors including gastrointestinal stromal tumors.
J Am Coll Surg 2006;202:623‑9.
17. Goettsch WG, Bos SD, Breekveldt‑Postma N, Casparie M, Herings RM,
Hogendoorn PC. Incidence of gastrointestinal stromal tumours
898 Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
is underestimated: Results of a nation‑wide study. Eur J Cancer
2005;41:2868‑72.
18. Güller U, Tarantino I, Cerny T, Schmied BM, Warschkow R.
Population‑based SEER trend analysis of overall and cancer‑specific
survival in 5138 patients with gastrointestinal stromal tumor. BMC
Cancer 2015;15:557.
19. Rubió J, Marcos‑Gragera R, Ortiz MR, Miró J, Vilardell L, Gironès J,
et al. Population‑based incidence and survival of gastrointestinal
stromal tumours (GIST) in Girona, Spain. Eur J Cancer 2007;43:144‑8.
20. Nilsson B, Bümming P, Meis‑Kindblom JM, Odén A, Dortok A,
Gustavsson B, et al. Gastrointestinal stromal tumors: The incidence,
prevalence, clinical course, and prognostication in the preimatinib
mesylate era – A population‑based study in Western Sweden. Cancer
2005;103:821‑9.
21. Kawanowa K, Sakuma Y, Sakurai S, Hishima T, Iwasaki Y, Saito K,
et al. High incidence of microscopic gastrointestinal stromal tumors
in the stomach. Hum Pathol 2006;37:1527‑35.
22. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations
are common in incidental gastrointestinal stromal tumors one
centimeter or less in size. Am J Pathol 2002;160:1567‑72.
23. Caterino S, Lorenzon L, Petrucciani N, Iannicelli E, Pilozzi E,
Romiti A, et al. Gastrointestinal stromal tumors: Correlation between
symptoms at presentation, tumor location and prognostic factors in
47 consecutive patients. World J Surg Oncol 2011;9:13.
24. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF.
Two hundred gastrointestinal stromal tumors: Recurrence patterns
and prognostic factors for survival. Ann Surg 2000;231:51‑8.
25. Sorour MA, Kassem MI, Ghazal Ael‑H, El‑Riwini MT, Abu Nasr A.
Gastrointestinal stromal tumors (GIST) related emergencies. Int J
Surg 2014;12:269‑80.
26. Bucher P, Villiger P, Egger JF, Buhler LH, Morel P. Management of
gastrointestinal stromal tumors: From diagnosis to treatment. Swiss
Med Wkly 2004;134:145‑53.
27. Graadt van Roggen JF, van Velthuysen ML, Hogendoorn PC. The
histopathological differential diagnosis of gastrointestinal stromal
tumours. J Clin Pathol 2001;54:96‑102.
28. Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal
tumors: A study of 27 cases. Arch Pathol Lab Med 2000;124:1471‑5.
29. Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H,
et al. NCCN Task Force report: Management of patients with
gastrointestinal stromal tumor (GIST) – Update of the NCCN clinical
practice guidelines. J Natl Compr Canc Netw 2007;5 Suppl 2:S1‑29.
30. Wong NA. Gastrointestinal stromal tumours – An update for
histopathologists. Histopathology 2011;59:807‑21.
31. Lee CH, Liang CW, Espinosa I. The utility of discovered on
gastrointestinal stromal tumor 1 (DOG1) antibody in surgical
pathology‑the GIST of it. Adv Anat Pathol 2010;17:222‑32.
32. ESMO/European Sarcoma Network Working Group. Gastrointestinal
stromal tumors: ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow‑up. Ann Oncol 2012;23 Suppl 7:vii49‑55.
33. Kakkar A, Mathur SR, Jain D, Iyer VK, Nalwa A, Sharma MC. Utility
of DOG1 immunomarker in fine needle aspirates of gastrointestinal
stromal tumor. Acta Cytol 2015;59:61‑7.
34. Emory TS, Sobin LH, Lukes L, Lee DH, O’Leary TJ. Prognosis of
gastrointestinal smooth‑muscle (stromal) tumors: Dependence on
anatomic site. Am J Surg Pathol 1999;23:82‑7.
35. Wu PC, Langerman A, Ryan CW, Hart J, Swiger S, Posner MC. Surgical
treatment of gastrointestinal stromal tumors in the imatinib (STI‑571)
era. Surgery 2003;134:656‑65.
36. Pierie JP, Choudry U, Muzikansky A, Yeap BY, Souba WW, Ott MJ. The
effect of surgery and grade on outcome of gastrointestinal stromal
tumors. Arch Surg 2001;136:383‑9.
37. Cao H, Zhang Y, Wang M, Shen DP, Sheng ZY, Ni XZ, et al. Prognostic
analysis of patients with gastrointestinal stromal tumors: A single
unit experience with surgical treatment of primary disease. Chin
Med J (Engl) 2010;123:131‑6.
[Downloaded free from http://www.cancerjournal.net on Saturday, September 14, 2019, IP: 190.81.164.37]
El‑Menyar, et al.: Gastrointestinal stromal tumors
38. Dematteo RP, Gold JS, Saran L, Gönen M, Liau KH, Maki RG, et al. Tumor
mitotic rate, size, and location independently predict recurrence after
resection of primary gastrointestinal stromal tumor (GIST). Cancer
2008;112:608‑15.
39. Kargin S, Çakir M, Gündes E, Yavuz Y, Esen HH, Sinan Iyisoy M, et al.
Relationship of preoperative neutrophil lymphocyte ratio with
prognosis in gastrointestinal stromal tumors. Ulus Cerrahi Derg
2015;31:61‑4.
40. Emile JF, Théou N, Tabone S, Cortez A, Terrier P, Chaumette MT, et al.
Clinicopathologic, phenotypic, and genotypic characteristics of
gastrointestinal mesenchymal tumors. Clin Gastroenterol Hepatol
2004;2:597‑605.
41. Martín J, Poveda A, Llombart‑Bosch A, Ramos R, López‑Guerrero JA,
García del Muro J. Deletions affecting codons 557‑558 of the c‑KIT
gene indicate a poor prognosis in patients with completely resected
gastrointestinal stromal tumors: A study by the Spanish Group for
Sarcoma Research (GEIS). J Clin Oncol 2005;23:6190‑8.
42. Bachet JB, Hostein I, Le Cesne A, Brahimi S, Beauchet A,
Tabone‑Eglinger S, et al. Prognosis and predictive value of KIT exon
11 deletion in GISTs. Br J Cancer 2009;101:7‑11.
43. Andersson J, Bümming P, Meis‑Kindblom JM, Sihto H, Nupponen N,
Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions
are associated with poor prognosis. Gastroenterology 2006;130:1573‑81.
44. Cho S, Kitadai Y, Yoshida S, Tanaka S, Yoshihara M, Yoshida K, et al.
Deletion of the KIT gene is associated with liver metastasis and poor
prognosis in patients with gastrointestinal stromal tumor in the
stomach. Int J Oncol 2006;28:1361‑7.
45. Rubin BP. Gastrointestinal stromal tumours: An update. Histopathology
2006;48:83‑96.
46. Tornillo L, Terracciano LM. An update on molecular genetics of
gastrointestinal stromal tumours. J Clin Pathol 2006;59:557‑63.
47. Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M,
Segal NH, et al. Gene expression in gastrointestinal stromal tumors
is distinguished by KIT genotype and anatomic site. Clin Cancer Res
2004;10:3282‑90.
48. Sun XC, Yan JY, Chen XL, Huang YP, Shen X, Ye XH. Depletion
of telomerase RNA inhibits growth of gastrointestinal tumors
transplanted in mice. World J Gastroenterol 2013;19:2340‑7.
49. Agaimy A. Gastrointestinal stromal tumors (GIST) from risk
stratification systems to the new TNM proposal: More questions
than answers? A review emphasizing the need for a standardized
GIST reporting. Int J Clin Exp Pathol 2010;3:461‑71.
50. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al.
Diagnosis of gastrointestinal stromal tumors: A consensus approach.
Hum Pathol 2002;33:459‑65.
51. Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG.
Gastrointestinal stromal tumors in Iceland, 1990‑2003: The Icelandic
GIST study, a population‑based incidence and pathologic risk
stratification study. Int J Cancer 2005;117:289‑93.
52. Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M,
et al. Prognostic significance of expressions of cell‑cycle regulatory
proteins in gastrointestinal stromal tumor and the relevance of the
risk grade. Hum Pathol 2005;36:828‑37.
53. Rutkowski P, Nowecki ZI, Michej W, Debiec‑Rychter M, Wozniak A,
Limon J, et al. Risk criteria and prognostic factors for predicting
recurrences after resection of primary gastrointestinal stromal tumor.
Ann Surg Oncol 2007;14:2018‑27.
54. Takahashi T, Nakajima K, Nishitani A, Souma Y, Hirota S, Sawa Y,
et al. An enhanced risk‑group stratification system for more practical
prognostication of clinically malignant gastrointestinal stromal
tumors. Int J Clin Oncol 2007;12:369‑74.
55. Joensuu H. Risk stratification of patients diagnosed with
gastrointestinal stromal tumor. Hum Pathol 2008;39:1411‑9.
56. Miettinen M, Lasota J. Gastrointestinal stromal tumors: Pathology
and prognosis at different sites. Semin Diagn Pathol 2006;23:70‑83.
57. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors
Journal of Cancer Research and Therapeutics - Volume 13 - Issue 6 - October-December 2017
of the stomach: A clinicopathologic, immunohistochemical, and
molecular genetic study of 1765 cases with long‑term follow‑up.
Am J Surg Pathol 2005;29:52‑68.
58. Goh BK, Chow PK, Yap WM, Kesavan SM, Song IC, Paul PG, et al. Which
is the optimal risk stratification system for surgically treated localized
primary GIST? Comparison of three contemporary prognostic criteria
in 171 tumors and a proposal for a modified Armed Forces Institute
of Pathology risk criteria. Ann Surg Oncol 2008;15:2153‑63.
59. Sanchez Hidalgo JM, Rufian Peña S, Ciria Bru R, Naranjo Torres A,
Muñoz Casares C, Ruiz Rabelo J, et al. Gastrointestinal stromal
tumors (GIST): A prospective evaluation of risk factors and prognostic
scores. J Gastrointest Cancer 2010;41:27‑37.
60. Gold JS, Gönen M, Gutiérrez A, Broto JM, García‑del‑Muro X, Smyrk TC,
et al. Development and validation of a prognostic nomogram for
recurrence‑free survival after complete surgical resection of localised
primary gastrointestinal stromal tumour: A retrospective analysis.
Lancet Oncol 2009;10:1045‑52.
61. Woodall CE 3 rd , Brock GN, Fan J, Byam JA, Scoggins CR,
McMasters KM, et al. An evaluation of 2537 gastrointestinal
stromal tumors for a proposed clinical staging system. Arch Surg
2009;144:670‑8.
62. Edge SB, Compton CC. The American joint committee on cancer: The
7th edition of the AJCC cancer staging manual and the future of TNM.
Ann Surg Oncol 2010;17:1471‑4.
63. Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY; ESMO Guidelines
Working Group. Gastrointestinal stromal tumours: ESMO clinical
recommendations for diagnosis, treatment and follow‑up. Ann Oncol
2009;20 Suppl 4:64‑7.
64. Gervaz P, Huber O, Morel P. Surgical management of gastrointestinal
stromal tumours. Br J Surg 2009;96:567‑78.
65. Karakousis GC, Singer S, Zheng J, Gonen M, Coit D, DeMatteo RP,
et al. Laparoscopic versus open gastric resections for primary
gastrointestinal stromal tumors (GISTs): A size‑matched comparison.
Ann Surg Oncol 2011;18:1599‑605.
66. Liang JW, Zheng ZC, Zhang JJ, Zhang T, Zhao Y, Yang W, et al.
Laparoscopic versus open gastric resections for gastric gastrointestinal
stromal tumors: A meta‑analysis. Surg Laparosc Endosc Percutan Tech
2013;23:378‑87.
67. Koh YX, Chok AY, Zheng HL, Tan CS, Chow PK, Wong WK, et al.
A  systematic review and meta‑analysis comparing laparoscopic
versus open gastric resections for gastrointestinal stromal tumors
of the stomach. Ann Surg Oncol 2013;20:3549‑60.
68. Buchs NC, Bucher P, Pugin F, Hagen ME, Morel P. Robot‑assisted
oncologic resection for large gastric gastrointestinal stromal
tumor: A preliminary case series. J Laparoendosc Adv Surg Tech A
2010;20:411‑5.
69. Desiderio J, Trastulli S, Cirocchi R, Boselli C, Noya G, Parisi A, et al.
Robotic gastric resection of large gastrointestinal stromal tumors.
Int J Surg 2013;11:191‑6.
70. Intuitive Surgical, Inc. The da Vinci Surgery Experience; 2014.
Available from: http://www.davincisurgery.com/assets/docs/
da‑vinci‑surgery‑fact‑sheet‑en‑1005195.pdf?location=1&version=b.
[Last accessed on 2016 Jan 13].
71. Ortiz‑Oshiro E, Exposito PB, Sierra JM, Gonzalez JD, Barbosa DS,
Fernandez‑Represa JA. Laparoscopic and robotic distal gastrectomy
for gastrointestinal stromal tumour: Case report. Int J Med Robot
2012;8:491‑5.
72. Moriyama H, Ishikawa N, Kawaguchi M, Hirose K, Watanabe G.
Robot‑assisted laparoscopic resection for gastric gastrointestinal
stromal tumor. Surg Laparosc Endosc Percutan Tech 2012;22:e155‑6.
73. Hashizume M, Sugimachi K. Robot‑assisted gastric surgery. Surg Clin
North Am 2003;83:1429‑44.
74. Song J, Oh SJ, Kang WH, Hyung WJ, Choi SH, Noh SH. Robot‑assisted
gastrectomy with lymph node dissection for gastric cancer: Lessons
learned from an initial 100 consecutive procedures. Ann Surg
2009;249:927‑32.
899
[Downloaded free from http://www.cancerjournal.net on Saturday, September 14, 2019, IP: 190.81.164.37]

El‑Menyar, et al.: Gastrointestinal stromal tumors

75. Patriti A, Ceccarelli G, Bellochi R, Bartoli A, Spaziani A, Di Zitti L,
et al. Robot‑assisted laparoscopic total and partial gastric resection
with D2 lymph node dissection for adenocarcinoma. Surg Endosc
2008;22:2753‑60.
76. Leach, B. Expanded Use of Gleevec Approved in Patients with
GIST – Onclive.com; 2014 Available from:  http://www.onclive.com/
web-exclusives/Prolonged-Use-of-Imatinib-in-GIST-Patients-Leads-to-
New-FDA-Approval. [Last accessed on 2016 Jan 13].
77. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B,
Fletcher JA, et al. Long‑term results from a randomized phase II
trial of standard‑ versus higher‑dose imatinib mesylate for patients
with unresectable or metastatic gastrointestinal stromal tumors
expressing KIT. J Clin Oncol 2008;26:620‑5.
78. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW,
Demetri GD, et al. Adjuvant imatinib mesylate after resection of
localised, primary gastrointestinal stromal tumour: A randomised,
double‑blind, placebo‑controlled trial. Lancet 2009;373:1097‑104.
79. Yip D, Zalcberg J, Ackland S, Barbour AP, Desai J, Fox S, et al.
Controversies in the management of gastrointestinal stromal tumors.
Asia Pac J Clin Oncol 2014;10:216‑27.
80. Al‑Thani H, El‑Menyar A, Rasul KI, Al‑Sulaiti M, El‑Mabrok J,
Hajaji K, et al. Clinical presentation, management and outcomes of
gastrointestinal stromal tumors. Int J Surg 2014;12:1127‑33.
81. Current Clinical Trials for GIST Cancer. Available from: http://www.
gistsupport.org/treatments‑for‑gist/clinical‑trials/current‑trials.
php. [Last accessed on 2016 Jan 13].

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