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Mesenchymal tumors are the most common submucosal
tumors of the gastrointestinal tract. However, they comprise
only about 1% of all gastrointestinal tumors (1-3). Based
on a histological resemblance to smooth muscle, these tumors
were originally referred to as leiomyomas, leiomyoblastomas,
and leiomyosarcomas (1-5). This terminology continues to be
commonly used. Detailed structural studies using immunohistochemical
staining with molecular markers have demonstrated that the
cell of origin of these neoplasms is possibly the interstitial
cell of Cajal (6-11). These submucosal stromal tumors can
now be classified into several subtypes based on differentiation
into neuronal and/or smooth muscle cell types. Therefore,
the preferred and correct terminology is now gastrointestinal
stromal tumor (GIST) to indicate that the phenotypic origin
of these neoplasms may be uncertain. The terms leiomyoma,
leiomyoblastoma, and leiomyosarcoma should be avoided in most
cases, unless the tumor has been extensively characterized
by immunohistochemical staining.
The majority of these neoplasms are asymptomatic
and are discovered incidentally during endoscopic or radiologic
examinations. They occur in equal frequency in men and women,
generally after the fifth decade (1-5). The overlying mucosa
usually appears smooth and normal at endoscopy (Figure 1).
Large tumors may outgrow their blood supply, ulcerate, and
present with gastrointestinal bleeding (Figure 2). GISTs may
also present with obstructive symptoms, especially if they
are located at the cardia (Figure 3) or near the pylorus.
Pain and weight loss, often associated with very large GISTs,
are symptoms that suggest malignancy. However, benign GISTs
may also be large and the differential diagnosis is clinically
difficult. Histologic diagnosis of GIST is usually not possible
by endoscopic biopsy because these neoplasms are located below
the submucosa and are quite firm.
The differentiation of benign and malignant
GISTs is difficult even after the tumor has been surgically
resected. Pathological series have reported a malignancy rate
of 13 to 56% in resected tumors (1-5) A combination of pathological
criteria, which includes size of neoplasm, mitotic rate (>
4 mitoses per high power field are associated with malignancy),
tumor cell necrosis, increased cellularity, cellular atypia,
and invasion into adjacent organs are used to help diagnose
malignancy (11, 25, 29).
Because large tumors may be benign and tumors with a low mitotic
rate may metastasize, even expert pathologists cannot predict
the behavior of all GISTs after resection.
Endosonography (EUS) has become an invaluable
imaging modality for the clinical diagnosis of GIST and for
differentiating these neoplasms from other submucosal lesions
(12-16). At EUS, GISTs are characterized by a hypoechoic appearance
(Figure 4) and can be seen to originate from the fourth hypoechoic
endosonographic layer (muscularis propria). They are generally
ovoid or elliptical in shape but may be multilobular or pedunculated.
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EUS features that should be characterized
when imaging a GIST include regularity of the extraluminal
border (Figure 5), presence of cystic spaces (Figure 6), echogenic
foci (Figure 7), heterogeneity and size (17-20). An irregular
extraluminal border (Figure 8) is likely associated with an
invasive tumor, cystic areas likely represent cellular necrosis,
and echogenic foci are likely caused by fibrosis (17). These
histopathological features along with size are criteria that
are used to diagnose malignancy. The corresponding EUS features
along with endosonographic measurements of size also appear
to be able to differentiate benign GISTs from malignant ones.
If multiple EUS features are present in a large GIST (>3
or 4 cm), then the neoplasm is likely malignant, and if a
GIST is < 3 cm in size, homogeneous, and smooth, it is
likely benign. The behavior of a GIST that is < 4 cm in
size and contains one or two of the EUS features is difficult
to predict. One must remember that the EUS interpretation
of these features is dependent on the endosonographer and
is subject to a fair degree of inter-observer variability
(17).
Multiple investigators have attempted to
use EUS guidance to obtain diagnostic histological material
(21-24). Unfortunately, fine needle aspiration of these lesions
has not been very successful. Firstly, because they are very
firm, a large amount of force is required to penetrate the
neoplasm with a narrow gauge needle. Secondly, the neoplasms
may be fibrotic and it may be difficult to obtain cytological
material by aspiration. Finally, because the diagnosis of
malignancy is dependent on histology and architecture, even
if an adequate cytological specimen is obtained by EUS guided
fine needle aspiration, a reliable diagnosis of a benign GIST
cannot be made. A guillotine needle that permitted endoscopic
biopsies of GISTs and obtained a core specimen was developed
(21). However, it did not gain in popularity, probably because
of concern for bleeding and difficulty in use. A recent pilot
investigation (25) demonstrated that immunohistochemical staining
using CD34, c-kit, and Ki-67 labeling index was able to diagnose
GISTs preoperatively but the diagnosis of malignancy in this
study was still based on tumor size and mitotic index. If
other investigators confirm these results in larger studies,
then this methodology might provide a pre-operative method
for the histological diagnosis of GISTs. Large bore and Trucut
needles being developed for EUS use may further enhance the
ability to obtain a core of tissue from within these firm
neoplasms. However, given that pathologists have difficulty
in determining the behavior of a GIST even after the entire
specimen has been resected, it remains unclear whether improved
techniques for obtaining tissue under EUS guidance will improve
clinical decision making.
Conclusion
Surgical resection is the only treatment
that is effective for symptomatic GISTs. Surgery should also
be performed on incidental GISTs that are large or have several
EUS features associated with malignancy. GISTs that appear
benign at EUS can be safely observed. The frequency with which
characteristically benign asymptomatic lesions should be re-imaged
has not been determined but is likely in the order of several
years. It is difficult to decide what to recommend to patients
who have GISTs that are indeterminate at EUS. These management
decisions should be made on a case-by-case basis. Gastric
tumors that are amenable should probably be considered for
laparoscopic excision, if the patient is a good surgical candidate.
Esophageal GISTs are more likely to be benign and should probably
be left alone, provided that they are not symptomatic. Excision
of duodenal tumors requires a more aggressive approach and
should only be attempted when there is a high suspicion of
malignancy. Colonic and rectal GISTs are unusual. Excision
of small rectal GISTs may sometimes be possible using a transanal
approach. Until recently, therapy of metastatic GISTs was
largely ineffective. However, the discovery that a large number
of GISTs are malignant because of the presence of a mutated
c-kit gene (26-28) and the availability of a specific chemotherapeutic
agent that targets this oncogene has led to remarkable advances
in the chemotherapy of this uncommon gastrointestinal malignancy.
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