Review Article
Current Management of Duodenal Gastrointestinal Stromal Tumors
Marcelo A. Beltrán1,2*
1Department of Surgery, Hospital de La Serena, Chile
2Department of Clinics, Universidad Católica del Norte, Chile
*Corresponding author: Marcelo A. Beltrán, Department of Surgery, La Serena Hospital, La Serena, IV Región, Chile
Published: 02 Dec, 2016
Cite this article as: Beltrán MA. Current Management of
Duodenal Gastrointestinal Stromal
Tumors. Clin Oncol. 2016; 1: 1156.
Abstract
Gastrointestinal stromal tumors (GISTs) originating in the duodenal wall constitute the most
challenging localization for this gastrointestinal neoplasm. Duodenal GISTs are relatively
uncommon. The prevalence of duodenal GIST is very low, accounting for 5% to 7% or less of all
surgically resected GISTs. Most published reports on duodenal GIST are case reports or small
case series. Consequently, the unspecific clinical manifestations, radiologic diagnosis, appropriate
surgical treatment, prognostic factors and survival constitute a subject of current controversy. This
review addresses the management of duodenal GISTs trying to establish and define surgical options
according to GIST localization within the duodenum. Most articles concerning duodenal GISTs
state that unlike tumors involving other sites of the gastrointestinal tract, the optimal procedure for
duodenal GISTs has not been well characterized in the surgical literature. However, when carefully
reviewing the published literature on the subject, it was possible to identify common surgical
approaches to duodenal GISTs which are fairly standard among different authors. All approaches
take into account the GIST localization within the duodenal wall and its anatomic relationships to
decide whether local resection or Whipple operation should be performed. Using this knowledge,
defined surgical options for duodenal GISTs according to their localization within the duodenum are
being proposed. Besides the current controversy regarding the indications for Whipple procedure,
the other most important issue remaining to be addressed is the implementation of laparoscopic
surgery for this challenging tumor.
Keywords: Duodenum; Gastrointestinal stromal tumors; GIST; Duodenal GIST; Duodenal tumors
Introduction
Gastrointestinal stromal tumors (GISTs) are defined as morphologically spindle cell, epitheloid, occasionally pleomorphic, mesenchymal tumors that usually arise from the gastrointestinal tract, express the KIT protein (c-kit), have a positive immunohistochemistry staining for CD117, and harbor a mutation of a gene that encodes for a type III receptor tyrosine kinase [1]. GISTs are known as such since 1983 [2]. In 1998 the role of c-kit in the pathology of GIST was defined [3], and in 2001 a major finding concerning the activity of imatinib mesilate against GIST was reported [4]. The current management of GIST includes surgery for local non-metastatic tumors, and a combination of imatinib and surgery for recurrent or metastatic GIST. Indications for imatinib therapy, besides recurrence and metastasis, are still controversial [1,5]. Recommended imaging studies include computed tomography (CT), magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) [5,6]. However, CT is widely available and is the imaging modality of choice for patients with suspected abdominal mass or biopsy proven GIST [5]. The incidence of GISTs varies from 10 to 20 cases per million people per year [5-11]. GISTs are the most common mesenchymal tumors of the gastrointestinal tract, accounting for 1% to 2% of all gastrointestinal neoplasms [1-7]. GISTs can occur in any part of the digestive tract, are more common in the stomach (50% to 70%), followed by the small bowel (20% to 30%), colon, rectum and appendix (0.5% to 10%), esophagus (1%), and some rare cases in the pancreas, gallbladder, mesentery, greater and lesser omentum, and retroperitoneum [1-10]. Duodenal GISTs are relatively uncommon. The prevalence of duodenal GIST is very low, accounting for 5% to 7% or less of all surgically resected GISTs; however, they represent nearly 30% of all primary duodenal tumors [7]. Most published reports on duodenal GIST are case reports or small case series [7-21]. Consequently, the unspecific clinical manifestations, radiologic diagnosis, appropriate surgical treatment, prognostic factors and survival constitute a subject of controversy. This review addresses the current management of duodenal GISTs trying to establish and define surgical options according to GIST location within the duodenum.
Table 1
Biology of Gist
GISTs are neoplasms arising from the interstitial cells of Cajal which form a cellular network around the myenteric plexus and within the muscularis propria of the gastrointestinal wall [1-8]. Most GISTs are comprised of a fairly uniform population of spindle cells (70% of cases), others are dominated by epitheloid cells (20% of cases), and the remainder 10% consists of a mixture of spindle and epitheloid cells [8,9]. The cell morphology varies by site, by the type of KIT mutation, and by the platelet-derived growth factor receptors-α (PDGFR-α) genes. GIST with PDGFR-α mutations are nearly exclusive gastric in origin and are mostly the epitheloid variants [10- 12]. Approximately 86% to 95% stain positively for c-kit (CD117); 80% for BCL-2; 70% to 81% for CD34; 35% to 70% for smooth muscle actin; 10% to 38% for S-100, and 5% or less for desmin [1-9]. A recently characterized gene encoding DOG1 protein has been stained by the anti-DOG1 antibody and has been found useful in staining GISTs possessing either KIT or PDGFR-α mutations [10]. Either KIT or PDGFR-α mutation are found in over 95% of adult GISTs [10,11]. KIT, encoded by the c-kit gene, is a 145-kD transmembrane glycoprotein member of the subclass III family of receptor tyrosine kinases, that serves as the receptor for SCF and tyrosine kinase and is structurally similar to PDGFRs-α and –β, colony-stimulating factor-1 receptor (CSF-1R), and FMS-like tyrosine kinase-3 (FLT-3) [9,10]. KIT function is critical to the development of the interstitial cells of Cajal, hematopoietic progenitor cells, mast cells and germinative cells. KIT mutation is an early event in GIST development [10]. Mutations of the juxtamembrane domain or exon 11 have been reported with a frequency between 20% and 92%; however, the incidence is around 66%. Deletions and insertions affect the codons 557 to 559. Point mutations are limited to four codons: 557, 559, 560 and 576. Internal tandem duplications are observed near the end of the exon. Mutations in the extracellular domain or exon 9 are most frequent in small bowel GISTs (95%), and have been found in 10% to 18% of all cases. Mutations in the activation loop or exon 17 are rare and have been reported in 0.6% of cases [9]. In approximately 10%, no KIT mutations are found even if the whole coding region is examined [10]. Most duodenal GISTs have mutations of exon 11 (40% to 70%), other frequently found mutations were located on exon 9 (13% to 31%) and exon 13 (11%). Wild type GISTs with no mutations are found in 10% to 15%. The importance of KIT mutations lies in the prognosis associated to more aggressive mutations such as the mutations of exon 11 which are present in high-risk GITSs, while mutations of exon 9 have been related to malignant GISTs [9] (Table 1).
Table 2
Table 3
Clinical Presentation
GISTs have been diagnosed in all-age patients, but most tumors
show clinical manifestations around 60 years of age. They are more
frequent in male patients (68% to 80%) [7-21]. Because of the lack
of specific clinical manifestations, early detection of duodenal GISTs
is difficult. At the time of diagnosis the tumors are between 1 cm
and 32 cm in diameter, and may cause mass-related symptoms or
anemia as a result of hemorrhage secondary to mucosal ulceration
[13-21]. Duodenal GISTs are frequently asymptomatic lesions and
are discovered incidentally during radiologic imaging for unrelated
conditions and during elective or emergency surgery for other
causes [13-23]. Duodenal GISTs most frequently involve the second
portion of the duodenum, followed in order by the third, fourth and first duodenal portion [7-20] (Table 2). Despite the fact that the
duodenum is an uncommon location for the occurrence of GIST
and the prevalence is around 5% or less [7,18], some authors have
reported an incidence between 6% and 29% in series comprising
GISTs in all locations and series of GISTs located specifically in the
small-bowel [16,17,19].
The most common symptoms of duodenal GISTs are hemorrhage
and abdominal pain [17-20]. However, many are asymptomatic (Table
3). Most duodenal GISTs present with upper digestive hemorrhage,
either macroscopic or occult [19-21]. The cause of hemorrhage in
endoluminal growing GISTs is the formation of an ulcer at the dome
of the tumor; frequently, these tumors are small endophytic lesions
measuring less than 5 cm [18,19]. Abdominal pain is more likely to
be present in large exophytic tumors, and is due to the mass effect
and compression on other organs [19]. According to the established
criteria for risk of progression [22] (Table 4), duodenal GISTs presents
with very-low risk in 8%, low risk in 31%, and high risk in 69% [21].
At the time of presentation, most tumors are solitary (89%) [19].
Duodenal gist in patients with neurofibromatosis Type I
GISTs have been described in the setting of Carney´s triad,
Carney-Stratakis syndrome, and Neurofibromatosis Type 1 (NF1)
[9,10,21-24]. Most GISTs are generally sporadic but 5% occur in
the context of a familial syndrome or NF1 [21]. In familial GIST
remarkable hyperplasia of the interstitial cells of Cajal is observed
in the small and large intestines. Normally, the interstitial cells of
Cajal comprises one or two cell layers, whereas hyperplasia of 10 to
20 cells layers is observed in familial GIST patients [10]. Duodenal
GISTs are an uncommon occurrence in NF1, in these patients are
frequently multifocal and located in the small bowel, more commonly
in the ileum [23-26]. NF1 was described in 1882 by Frederick von
Recklinghausen, and is one of the most common genetic disorders,
with a frequency of 1:2500 to 1:5000 births [23-26]. Inherited in an
autosomal dominant pattern with variable penetrance, the genetic
abnormality has been localized to the long arm of chromosome 17
(17q11.2). This gene encodes neurofibromin, a cytoplasmic protein
which controls cellular proliferation by inactivating the p21 ras
and the MAP kinase pathway [25]. The type of GIST developing in NF1 results from the genetic inactivation of neurofibromin. Since
neurofibromin suppresses the ras-MAP kinase cascade, the cause of
GIST in NF1 appears to be hyperactivation of the ras-MAP kinase
cascade [10]. Gastrointestinal associations of NF1 have been well
described, but the true incidence of GISTs and the proportion of these
becoming clinically significant are not known [26]. Patients with NF1
have a high risk to develop GISTs (7%) [23]. Based on retrospective
reviews and postmortem examination studies, some have estimated
that 10% to 60% of patients with NF1 have gastrointestinal tumors,
although less than 5% actually have any associated symptomatology
[24]. Gastrointestinal complications arise during midlife, occurring
in four principal forms: hyperplasia of the gut neural tissue,
multiple GISTs, duodenal or periampullary endocrine tumors, and
a miscellaneous group of other tumors [23-26]. GISTs associated
with NF1 tend to be multiple, with some tumors being malignant and
others benign and present with abdominal pain, palpable abdominal
mass, bowel obstruction, intussusception, volvulus, perforation, and
gastrointestinal hemorrhage [23-26].
Table 4
Table 5
Diagnosis
Endoscopy
The first and second portions of the duodenum are accessible by
conventional endoscopy. Most duodenal GISTs located within the
first and second duodenal portion can be detected with endoscopy
[17]. At endoscopy, GISTs appear as submucosal sharply demarcated
elevated tumors, occasionally ulcerated [7,18,21]. Sometimes, small,
less than 2 cm ulcerated duodenal GISTs have been mistaken by the
papilla of Vater and hemobilia has been suspected [18]. Endoscopic
biopsy rarely yields a correct diagnosis, and most times shows only
chronic inflammation or normal mucosa; however, some have
reported an accuracy of 21% to correctly diagnose duodenal GISTs
[7].
Duodenography
Duodenography may be a useful study showing the endoluminal
growth of the tumor or external compression by extraluminal growth
[15,17].
Computed tomography
The best radiologic study to identify and diagnose duodenal GISTs
is abdominal computed tomography (CT). Practically all duodenal
GISTs can be detected by CT [17,18]. GISTs are hypervascular
tumors appearing as well-defined endophytic or exophytic masses
on contrast enhanced images, the tumor is strongly enhanced in the
arterial phase and this enhancement may last until the delayed venous
phase [15,27,28]. Large tumors tend to have mucosal ulceration and
present as well-enhanced, well-demarcated, lobulated, heterogeneous
mass which may have central necrosis and cavitation with cystic and necrotic components combined with intraluminal and extraluminal
tumor growth [7,17,27,28,30,31]. Small tumors are depicted as
sharply delineated smooth oval or round homogeneous masses with
moderate or high contrast enhancement [15,27,28,31,32] (Figure 1).
The CT criteria used to describe and categorize GISTs was published
by Burkill et al. in 2003 [28,29] (Table 5). Most GISTs present
as exophytic, well-defined, round or oval lesions [27,29,30,33].
Heterogeneous characteristics, due to the presence of necrosis or fluid, are commonly seen in larger tumors, compared with smaller tumors
which habitually are homogeneous masses [28,29] (Figure 2 and 3).
Malignant GISTs presents with distant metastasis most commonly
to the liver or with local invasion of surrounding tissues and organs
[27-34]. Table 6 depicts the tomographic characteristics described
by various authors [27-34]. The differential diagnosis includes
other soft tissue tumors including leiomyoma, leiomiosarcoma,
fibrosing mesenteritis, mesenteric lymphangioma, plexiform
neurofibromatosis, ectopic pancreas, and malignant tumors of nerve
sheath and vascular origin [28-30].
Magnetic resonance
Magnetic resonance images (MRI) are comparable to CT images
[17,29]. On MRI, solid GISTs have a low signal intensity on T1-
weighted images and high signal intensity on T2-weighted images
[7,15,32]. Necrosis and hemorrhage within the tumor can influence
the signal intensity of MRI images [17]. The administration of
gadolinium enhances the intensity of T2-weighted images [32].
Endosonography
This study, while not widely available, should be used to identify
the exact location of the tumor within the duodenal wall and its
relationships with adjacent structures, mainly the papilla of Vater and
the pancreatic head.
Neoadjuvant therapy
The first successful small-molecule inhibitor was imatinib mesilate,
which was initially developed as a specific inhibitor of PDGFR [35].
Posteriorly it was found to be a potent inhibitor of wild-type KIT
and various types of mutated KIT found in GISTs [10,35,36]. GIST
patients with mutations in exon 11 have the best response, whereas the
few patients without either KIT or PDGFRα mutations do not have
a response to imatinib [35,36]. Complete responses to imatinib have
not been observed in patients with GIST [35]. The first clinical report
of successful use of imatinib mesilate in the treatment of a patient was
published in 2001 [4], afterwards a rapid development of clinical trials
[36], prompted the approbation of imatinib mesilate by the United
States Food and Drug Administration for the treatment of GIST in
2002 [10]. The indications for neoadjuvant therapy with imatinib are;
downsizing large GISTs in order to attempt surgery [10,37], and the
treatment of advanced or metastatic tumors [36]. In selected cases of
locally advanced or marginally resectable primary GISTs, the strategy
of cytoreduction with neoadjuvant imatinib therapy has become
a common, established and approved approach [38-40]. The use of
neoadjuvant imatinib in routine practice associated to surgery has
excellent long-term results, as has been demonstrated by the largest trial on patients with GISTs, of whom 10% had duodenal tumors [38].
Indications for neoadjuvant imatinib therapy: Complete
resection of large GISTs is sometimes difficult for technical reasons.
In such cases, neoadjuvant therapy with imatinib has been attempted
[19,37,38]. The candidates for preoperative imatinib treatment are
those patients who may benefit from downsizing the tumor before
operation; this strategy is especially attractive in difficult locations
such as the duodenum, mainly the second and third portion, where
resection of the primary tumor may cause significant morbidity or
functional deficits [38]. After reducing the size of the tumor, it would
be successfully removed in 80% or more cases [37,38]. In large series
of duodenal GISTs, imatinib was applied preoperatively with good
results in patients affected with large high-risk tumors who will likely
undergo a complex procedure such as pancreatoduodenectomy
[19,20]. In these cases besides reducing the tumor size and because
primary tumors are fragile and hypervascular, preoperative
imatinib therapy may decrease the risk of bleeding, postoperative
complications, or tumor fragility and rupture [20,38]. Table 7
summarizes the current indications for neoadjuvant imatinib therapy
in duodenal GISTs.
Dose and management of neoadjuvant imatinib therapy: The
recommended dose of imatinib in the neoadjuvant setting is 400
mg daily until a maximal response is attained and confirmed with
two consecutive CT scans not showing further tumor regression or
until the surgeon deemed a radical organ sparing resection possible,
whichever condition was attained first [37,38]. The optimal duration
of preoperative therapy ranges from 4 to 12 months to achieve a
maximal dimensional response to imatinib. This is the time when a
plateau in tumor shrinkage is usually seen and the risk of development
of secondary resistance to therapy is still very low. At this time careful
response assessment with CT scans should be undertaken not to miss
the timing for surgery [38]. Postoperative imatinib adjuvant therapy
should be used routinely in patients considered for neoadjuvant
therapy [38].
Table 6
Figure 1
Figure 1
A) First portion duodenal GIST showing homogeneous
enhancement presenting in a 45 years-old woman. This tumor appeared
as a well-defined endophytic, sharply delineated, smooth oval rounded
homogeneous mass with moderate contrast enhancement. B) The tumor
measured 21 mm on diameter. The patient undergone laparoscopic
resection, including the first duodenal portion and part of the gastric antrum,
with Roux-en-Y reconstruction.
Figure 2
Figure 2
A) Second portion duodenal GIST showing heterogeneous strong
enhancement in the arterial phase, presenting in a 40 years-old woman.
This transversal CT view shows a heterogeneous, highly enhanced and well
defined tumor in the medial wall of the second duodenal portion infiltrating the
pancreatic head. The patient was resolved with Whipple procedure. B) Lateral
CT view showing the duodenal GIST measuring 4 cm on its lateral dimension.
C) Coronal view depicting the duodenal GIST measuring 3 cm on its frontal
dimension.
Figure 3
Figure 3
A) Coronal view showing a GIST in the lateral wall of the third
duodenal portion, measuring 3 cm on diameter, presenting in a 61 yearsold
woman. B) The tumor was well-defined, homogenous and highly
enhanced with contrast, depicting endophytic and exophytic growth. The
patient was treated with a wedge resection leaving a large defect on the
duodenal wall; reconstruction was achieved by a side-to-side Roux-en-Y
duodenojejunostomy.
Table 7
Table 8
Surgical Treatment
Complete surgical resection is the only curative treatment for GISTs [10,17,38,41-44]. Optimal surgical treatment entails complete
removal of the tumor with clear surgical margins, including adjacent
organs [43]. Due to the absence of lymph node metastasis or infiltrative
submucosal growth and because GISTs are well encapsulated
tumors that rarely have a tendency to local invasion, local excision
or segmental duodenectomy if feasible is sufficient and has been
associated to prolonged disease free survival [10-21,42,43,45].
Unlike GISTs involving other sites of the gastrointestinal tract, the
optimal surgical treatment for duodenal GISTs has not been wellcharacterized
and remains poorly defined in the surgical literature
[17,19,21]. Surgical removal of duodenal GISTs may be accomplished
by several options ranging from minimal to major procedures
[17,41,44,45]. The approach should be dictated by the location of
the lesion within the duodenum and the ability to achieve an R0
margin [19,42]. Conservative surgery constitutes local segmental
or wedge resection, and while technically feasible must be carefully
evaluated due to the complex duodenal anatomy and proximity to
crucial structures such as the papilla of Vater, pancreas, mesenteric
vessels, common biliary duct and pancreatic duct [7,19,20,25,43,45].
Consequently, local segmental or wedge resections are most times
difficult to perform, especially in the second portion [16,19]. In
clinical practice, 20% to 86% of duodenal GISTs have been reported
to be treated with pancreaticoduodenectomy [43]. Reported surgical
options for duodenal GISTs depend on tumor location and size
(Table 8) [15-21,23,24,41-53].
First duodenal portion
Large tumors located on the medial wall of the first duodenal
portion in close contact with the pancreatic head, should be treated
by pancreatoduodenectomy [16,19,20,24,25,41,42,44]. While those
GISTs located in the lateral wall if small, less than 2 or 3 cm, could
be treated by wedge resection with primary closure or segmental
resection with primary anastomosis including Billroth I procedure or
Roux-en-Y gastrojejunostomy [17,25,41,42,44,46] (Figure 4).
Second duodenal portion
The decision to perform a pancreatoduodenectomy in patients
with GISTs of the second duodenal portion is clearly influenced by the relationships of the tumor with the pancreatic head and the papilla
of Vater. Large or even small tumors located on the medial wall of the
second duodenal portion in close contact with the pancreatic head,
should be treated by pancreatoduodenectomy [16,19,20,24,25,37,41
,42,47,49]. Tumors located on the lateral wall of the second portion
can be subjected to local wedge resection with primary closure of
the duodenal wall, or distal duodenectomy including the tumor,
and reconstruction with lateral or terminal anastomosis between
the first jejunal loop and the duodenum, or Roux-en-Y anastomosis
between the duodenum and the jejunum [15,19,24,42,44,48] (Figure
5). However, the indication of segmental or wedge resection will be
dictated by the size of the tumor and the possibility to achieve R0
resection [44]. Anecdotally, re-implantation of the papilla of Vater in
a jejunal patch during segmental resection of the second portion of
the duodenum has been described [45]. Whenever the patency of the
ampulla of Vater is at risk or when the margin of the resection is very
close to this structure, a papilloplasty could be performed in order to
secure exocrine outflow through the papilla [50].
Third duodenal portion
Small or middle size tumors located on the medial or lateral wall of the third duodenal portion, may be treated by resection of
the third and fourth duodenal portions and primary end-to-end or
side-to-end anastomosis with the jejunum [44,51,52] (Figure 6A and
6B). In the case of wedge resection, primary closure may be attempted
[53]. In the case that primary closure would not be achieved, a Rouxen-
Y duodenojejunostomy could be performed [44] (Figure 6C and
6D). Large tumors located on the medial wall of the third duodenal
portions and in close contact with the pancreatic head or infiltrating
the pancreas should be treated with pancreatoduodenectomy
[19]. Tumors located on the lateral wall of the third portion can
be submitted to local wedge resection with primary closure of the
duodenal wall or Roux-en-Y anastomosis between the duodenum
and the jejunum [15,19,24,44].
Fourth duodenal portion
GISTs located on the fourth duodenal portion may be locally
resected and the intestinal transit restored by a primary end-to-end
or end-to-side anastomosis between the third duodenal portion and
jejunum [17,23,44] (Figure 7). Small tumors could be treated with
wedge resection [53].
Laparoscopic surgery
Laparoscopic surgery has been established in patients with
suspected gastric GIST and has been included within formal
therapeutic strategies to treat these tumors [54]. However,
laparoscopic resection of duodenal GIST has not been clearly
established and almost anecdotal experiences have been published,
including two first duodenal portion GISTs treated by wedge resection
and primary closure [17]. In our own experience, we have performed
a laparoscopic resection of a first duodenal portion GIST including
the first duodenal portion and the distal antrum, reconstructed by
a Roux-en-Y gastrojejunostomy with clear margins of more than 1
cm, and without surgical complications (Figure 1). Local segmental
or wedge resections of duodenal GISTs have been reported secure
and with excellent disease-free survival, consequently in selected
cases, laparoscopic resection may be attempted. Laparoscopic
pancreatoduodenectomy has been successfully described in malignant
and benign pancreatic tumors. Consequently, it makes sense to use
this approach to second portion duodenal tumors with indication
of Whipple resection. Nonetheless, most authors exclude duodenal
GISTs from laparoscopic resection [55].
Surgical controversies
Ultimately the decision to perform pancreatoduodenectomy
for duodenal GISTs depends not only on the localization, but also
on the tumor size [20,43]. Duodenal GISTs, which occur mostly in
the second duodenal portion, frequently present with a diameter of
more than 5 cm; consequently, they are more likely to be submitted
to a more complex procedure such as pancreatoduodenectomy
[19,20]. In Table 9, the differences and characteristics of GISTs
subjected to pancreatoduodenectomy and local resection are
depicted. Another subject of controversy is the necessity to perform
lymphadenectomy. Because GISTs do not spread via lymphatic
drainage, lymphadenectomy is not routinely performed, some authors
who had performed lymphadenectomy found metastasis in 2% or
less [19]. Regarding the necessity of concomitant procedures, they
should be performed in order to completely resect the tumor [43,44].
It has been found that the need of additional procedures is similar in
patients subjected to local resection or pancreatoduodenectomy, with
a frequency ranging from 4% to 31% [19,43].
Adjuvant therapy
Imatinib mesilate is considered the first line of therapy for the treatment of advanced GIST, improving disease-free survival and
overall survival [4,20,38]. Imatinib has been approved for adjuvant
therapy in patients after resection of primary GISTs with significant
risk of recurrence (400 mg daily) [38,56]. Sunitinib maleate is
considered second line therapy for imatinib-refractory GISTs [10].
Patients with high-risk tumors have a demonstrated benefit on
overall survival and disease-free survival by adjuvant treatment with
imatinib for 3 years, this indication is the currently standard of care
in such cases [20].
Imatinib resistance
Initial resistance to imatinib therapy ranges from 9% to 13% [56].
The oral bioavailability of imatinib decreases in patients with chronic
use. Imatinib resistance may be primary or secondary according to
the period of time from the onset of treatment to development of
metastases or local recurrence [56-59]. Early or primary resistance
develops within the first three months of treatment in 9% to 15% of
all patients. Late, acquired, or secondary resistance develops after
24 months of treatment in approximately 44% of all patients [57-
59]. Some prognostic risk factors to predict the response of GISTs
to imatinib has been identified. One of the most important is the
mutational status of KIT/PDGFR-α; patients with mutations in exons
11, 13 and 17 have a better response [57,59]. Other genes predicting
a good response are localized in the chromosome 19p corresponding
to the KRAB-ZNF91 complex [58]. About 85% to 90% of all GISTs
have primary active mutations of KIT and PDGFR-α generating
crucial diagnostic oncoproteins [57,58]. In patients with primary
or secondary resistance, secondary mutations in exons 9, 11, 14 and
17 of c-kit have been identified [57]. Mutations of exons 11 and 13
are related to primary resistance and mutations of exons 11 and 17
associates to secondary resistance [57,59,60]. Patients with metastatic
or recurrent GISTs initially responding to imatinib and afterwards
developing resistance must undergo early surgical exploration
because their chances of complete resection are higher [58-63]. The
use of increased doses of adjuvant imatinib after the second surgery
increases the chance of disease-free survival for at least 24 months,
without imatinib treatment the disease-free survival rarely surpasses
12 months [60,61]. Although recommendations for adjuvant therapy
have demonstrated benefit with continuous therapy for 3 years
[20], probably continuous treatment despite the risk of developing
resistance in patients with malignant GIST would prolong the
chance of disease-free survival [61]. A second generation of tyrosine-kinases inhibitors constituted by sunitinib has demonstrated its
utility in imatinib-resistant GISTs, particularly in those tumors with
mutations in exons 9, 13 and 14 associated to primary resistance
[64,65]. Eventually, sunitinib develops resistance [66,67], and in those
patients, only an aggressive surgical approach would bring the patient
a chance to overcome the disease [66,68]. Other currently available
imatinib-related medication with activity in imatinib-resistant GISTs
is nilotinib, which is also active in sunitinib-resistant tumors [69,70].
Figure 4
Figure 4
First duodenal portion GIST. Surgical procedures for GISTs located
in the first duodenal portion (D1).
A) Wedge resection with primary suture.
B) Segmental resection with primary anastomosis (including Billroth I
procedure).
C) Duodenal GIST requiring extensive segmental resection.
D) Reconstruction of an extensive first duodenal portion segmental resection
with Roux-en-Y gastrojejunal anastomosis.
Figure 5
Figure 5
Second duodenal portion GIST. Surgical procedures for GISTs
located in the second duodenal portion (D2).
A) Wedge resection.
B) Reconstruction of an extensive wedge resection of a second duodenal
portion GIST with Roux-en-Y duodenojejunostomy.
Figure 6
Figure 6
Third duodenal portion GIST. Surgical procedures for GISTs
located in the third duodenal portion (D3).
A) Distal duodenectomy including the third and fourth portions.
B) Reconstruction of distal duodenectomy with end-to-side
duodenojejunostomy.
C) Wedge resection of a third portion duodenal GIST.
D) Reconstruction of third portion duodenal GIST resection with Roux-en-Y
duodenojejunostomy.
Figure 7
Figure 7
Fourth duodenal portion GIST. Surgical procedures
for GISTs located in the fourth duodenal portion (D4).
A) Distal duodenectomy including the fourth portion.
B) Reconstruction with primary duodenojejunostomy.
Table 9
Table 10
Prognosis
Segmental or wedge resection of duodenal GISTs when feasible has been demonstrated to be sufficient and curative surgical treatment, with a satisfactory disease-free survival in series composed specifically of duodenal tumors [41-45]. In April 2001, the National Institutes of Health and the National Cancer Institute sponsored a consensus workshop which yielded guidelines that are still in use today. Thus, the prognosis and risk stratification of GIST was defined based on tumor size and mitotic index (Table 4). The survival for a primary tumor larger than 10 cm at 5 years has been estimated to be around 20%, whereas the survival for tumors less than 5 cm the survival could be approximately 47% to 65% [9,19,41]. Specifically, patients undergoing resection of localized tumors, have an overall survival of 98% at 3 years and 89% at 5 years; and disease-free survival of 67% at 3 years and 64% at 5 years [20]. The mitotic index Ki-67, has been linked to prognosis in a large number of studies and should be included in the evaluation of GISTs [16,17,41]. Even small GISTs with low mitotic activity may metastasize [10]. However, virtually all GISTs are associated with a risk of recurrence and approximately 40% to 50% of patients with potentially curative resections develop recurrent or metastatic disease [38]. Another prognostic feature is tumor location, habitually primary gastric tumors have a better prognosis and are less aggressive than those located in the small bowel or in the rectum [9,10,19]. Table 10 depicts various risk factors and predictors for recurrence described in studies of duodenal GISTs. Despite the ample knowledge of the biology of GISTs, these tumors behave somewhat erratically, even among low-risk GISTs recurrences have been reported 20 or more years after surgical resection [9]. In duodenal GISTs, recurrences have been described in 35% to 39% patients [21]. In high-risk tumors, recurrence is inevitable. In patients with a follow-up longer than 2 years, recurrence has been found in 19%, distant metastasis in 13% to 23%, local recurrence in 2% to 15%, and synchronous local and distant recurrence in 4% [19,21]. The most common site of distant metastasis is the liver [19,21,41]. Interestingly, after more than a decade of intensive research, the conclusion is the same as 10 years ago, the most important determinants of survival are mitotic count and tumor size [7,19,20,21,41,42,44].
Conclusion
Most articles concerning duodenal GISTs state that unlike tumors involving other sites of the gastrointestinal tract, the optimal surgical procedure for duodenal GISTs has not been well characterized in the literature. That is because clinical randomized trials has not been undertaken and published reports are mainly the experience of single or multiple specialized centers. However, when carefully reviewing the published literature on the subject, it was found out that surgical approaches to duodenal GISTs are fairly standard among different authors reporting from different countries and regions of the world. All take in account the localization of GIST within the duodenum and its anatomic relationships to decide whether local resections or pancreatoduodenectomy should be performed. Using this knowledge, defined surgical options for duodenal GISTs according to their localization have been proposed. Besides the controversy regarding the indications for pancreatoduodenectomy, probably the most important issue remaining to be addressed and defined is the implementation of laparoscopic surgery.
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