Christopher Fletcher Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts
A 37 year old woman presented in 1997 with acute abdominal pain. At laparotomy a 6 cm hemorrhagic mass was
found in the wall of the jejunum; the mass had "ruptured". Following excision, the patient did well for 2.5
years and then developed progressive abdominal fullness. CT scan revealed 3 large intra-abdominal masses
(ranging in size up to 40 cm) along with innumerable peritoneal nodules. A debulking procedure was
Neoplasms arising from the stromal (or mural) components of the gut can be divided broadly in two
categories. Some tumors are not unique to the gastrointestinal wall and appear similar to their
counterparts elsewhere - e.g. schwannomas, usual leiomyomas and (rare) leiomyosarcomas. The other category
comprises spindle cell and epithelioid neoplasms histologically resembling smooth muscle tumors but either
lacking (or presenting only limited) immunohistochemical and ultrastructural features of myogenic or neural
differentiation and for which prediction of behavior has proved to be problematic. This latter group, which
represent the substantial majority, are known as GI stromal tumors.
Stromal tumors of the gastrointestinal tract (GIST) occur over a wide age range but affect predominantly
middle aged and older individuals, with a slight female predominance. The biologic behavior of GISTs is
difficult to determine accurately from published data, given the different diagnostic criteria used, and the
tendency for late metastases in some cases, with spread sometimes occurring after 20 to 30 years. The
overall 5 and 10-year survivals of malignant GISTs, have been estimated at between 25 and 50%,1 although in
one series, only 10% of patients remained free of disease after a median follow-up of 68 months.2 Most such
patients succumb to disseminated intra-abdominal disease, although extra-abdominal spread may also occur.
GISTs were originally thought to arise from mural smooth muscle of the GI tract 3,4,5 Subsequently,
morphologic differences were noted between these "leiomyomas" and "leiomyosarcomas" of the gastrointestinal
tract and their counterparts in other sites: most gastrointestinal lesions appeared more cellular and the
tumor cells often had more ovoid or elongated nuclei and less brightly eosinophilic, rather fibrillary
cytoplasm. It also rapidly became clear that GISTs, unlike their apparent counterparts in other sites,
could metastasize despite the absence of usual histologic features of malignancy (in particular, in the
absence of significant mitotic activity) and that their behavior was much harder to predict.3,4,6 In the
1970s/early 1980s most ultrastructural studies failed to identify myofilaments with focal densities in the
majority of GISTs. In addition, several authors identified Schwannian or neuroaxonal characteristics in
some cases and, in 1984, a distinctive subset showing autonomic neural differentiation was first described.7
These were initially known as plexosarcoma, later as gastrointestinal autonomic nerve tumor (GANT)8 and are
now being subsumed once more into the general GIST category (see below). In the 1980s and early 1990s
numerous series of GIST were analysed immunohistochemically with inconsistent results. Although a large
proportion (between 30% to 80%) of GISTs have been shown to express muscle markers, the most specific of
those, desmin, has usually stained only a minority of tumors. Variable proportions of tumors with a neural
phenotype have been identified (from none to approximately 40%) and, interestingly, divergent
differentiation (coexpression of muscular and neural markers) was identified in up to 20% of cases.9 In the
early 1990s, CD34 was shown to stain up to 80% of GISTs, with or without markers of other specific
differentiation.10 Several authors tried (with little success) to correlate the immunophenotype of GISTs
with tumor location, the histologic appearance and, more importantly, with prognosis.
The difficulty in classifying GISTs into benign and malignant categories has long been recognized. In a
series of 87 GISTs, Kempson and Ranchod identified the mitotic count as the most useful indicator of
malignancy. However, while the presence of 5 or more mitoses per 10 HPF was closely correlated with
aggressive behavior, 40% of "leiomyosarcomas" had fewer mitotic figures.4 In order to refine the separation
of benign and malignant GISTs, numerous studies subsequently analyzed the correlation between malignancy and
various clinical and pathological parameters, often with variable results.11,12,13 The mitotic count has been
most widely accepted as the best histologic prognostic indicator4,18 and it has been shown that a high
mitotic count is associated with a shorter disease-free interval and shortened overall survival. Various
cutoff levels, separating benign, borderline and malignant categories have been proposed. However, because
of the overlap between clinically benign and malignant GISTs, and in view of the occurrence of metastasis in
histologically bland, mitotically inactive tumors, none of these has proven reliable in the management of
Tumor size has also been shown to be strongly correlated with metastasis.1,6 In Appelman's series of 127
cases, only one tumor < 6 cm metastasized.6 These results have been confirmed by most studies and, again,
various cutoff levels have been proposed, usually being set at around 5 and 6 cm. Unfortunately, as for the
mitotic count, some exceptions have been encountered, and, tumors as small as 2 cm have been reported to
metastasize14 and I have personally encountered a number of such cases.
Numerous other clinical, macroscopic and histologic parameters have been assessed, most of which have been
shown, at least in some univariate studies, to have some correlation with survival or the development of
metastases. Although the presence of unequivocal necrosis is usually regarded as highly suspicious for
malignancy, this has been reported in rare clinically benign cases. Ulceration of the overlying mucosa has
also been considered as a worrisome feature by some authors.15,16 Significant differences in terms of
outcome according to tumor site have only been observed in one study, in which the ten year survival reached
74% for gastric lesions, while it was only 17% for small bowel tumors.17
Because of this imperfect separation between benign and malignant GISTs using conventional pathologic
criteria, ancillary techniques such as evaluation of ploidy and proliferation markers were introduced in the
early 1990s. Most studies suggested that DNA ploidy correlates (by univariate analysis) with histologic
grade and that aneuploidy is associated with decreased survival. However, most authors compared tumor
ploidy with malignancy defined either clinically with limited follow-up or by histologic criteria. Most of
these studies included aneuploid cases that did not show clinical evidence of malignancy and, more
importantly, a few patients with diploid tumors (even of small size), developed disseminated disease.
Because of this overlap, ploidy does not appear to be more discriminant than morphology when applied in
individual cases. Similar problems have occurred with studies utilizing proliferation markers such as PCNA,
MIB-1 and AgNORs.
Most recently, in light of the considerable interest focused on GISTs as a consequence of the introduction
of effective therapy for relapsed lesions (see below), NIH convened a workshop in April 2001 with the goals
of better defining diagnostic and prognostic criteria for GIST.18 This led to the development of concensus
guidelines (shown in the table below),19 the key component of which is to think in terms of risk assessment,
rather than to label any of these lesions as definitely benign. Experience gained from currently ongoing
very large clinical trials of relapsed or metastatic GIST supports this approach.
Proposed Guidelines for Defining Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors19
Very low risk
< 2 cm
< 5 per 50 HPF
2 - 5 cm
< 5 per 50 HPF
< 5 cm 5 - 10 cm
6 - 10 per 50 HPF < 5 per 50 HPF
> 5 cm > 10 cm Any size
> 5 per 50 HPF Any mitotic rate > 10 per 50 HPF
C-Kit is a proto-oncogene encoding a transmembrane tyrosine-kinase receptor, KIT or CD 117 which plays an
important role in the development of melanocytes, germ cells, mast cells and the interstitial cells of Cajal
(ICCs). The latter, which are located between the muscular layers of the gastric and intestinal wall in
association with the myenteric plexus, are known to regulate autonomous peristaltic contraction and,
ultrastructurally, show features of both incomplete myogenic and neural differentiation. These cells are
characterized by dual immunopositivity for CD34 and CD 117. Recently, the hypothesis that GISTs might
differentiate towards an ICC phenotype, has been supported by extensive immunohistochemical, ultrastructural
and molecular studies20,21,22,23 and it has been demonstrated that immunoreactivity for CDl17 is seen in 85 to
100% of GISTs (whether spindle cell, epithelioid or mixed), while most other sarcomas or other neoplasms are
negative. In addition, activating c-kit mutations were identified in 5 of 6 cases from the original
series20 and our own personal experience with larger case numbers has been similar.24,25 The fact that
c-Kit plays a central role in tumor development or progression has received additional support with
identification of germline mutations in families with multiple GISTs.
CDl17-positive GISTs are also positive for CD34 in 60-70% of cases, and smooth muscle actin is positive in
15 to 30% of cases. Interestingly, all tumors showing immunohistochemical evidence of true smooth muscle
differentiation i.e. desmin positivity and diffuse actin positivity fail to stain for CD 117, further
justifying the separation of GISTs and conventional smooth muscle tumors. These findings have led to a
unifying concept, regarding GISTs as a morphologically (and immunophenotypically) heterogeneous group of
tumors characterized by CD 117 immunoreactivity and differentiating towards an ICC phenotype.19,23 GANTs in
our experience, are usually immunoreactive for CD 117 but often negative for CD34 and, in truth, fall within
the spectrum of GISTs, since they also show the same c-kit mutations.26
The recognition of GISTs as a cohesive but phenotypically heterogeneous group of tumors, defined by the
expression of KIT (CDl17), and their more objective separation from other mesenchymal neoplasms will allow
more reproducibility between studies and may help to refine our criteria for malignancy and/or prognostic
factors. The expression of KIT also appears as a useful adjunct in the diagnosis of those GISTs arising in
less usual sites, such as the mesentery, omentum or retroperitoneum,27 as well as in their separation from
other intra-abdominal neoplasms. Remarkably, a novel small molecule, STI-571 (Gleevec), which blocks the
receptor tyrosine kinase function of c-kit is already proving to be very effective in treatment of GISTs
which, until now have been regarded as a chemo-insensitive group of tumors. These remarkable results in
KIT-expressing GISTs (with appreciable responses in 60% or more of patients with uncontrolled local relapse
or metastasis) make it especially important for pathologists to use consistent diagnostic criteria in
conjunction with reproducible immunohistochemical stains.
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Tworek JA, Appelman HD, Singleton HP, Greenson JK. Stromal tumors of the jejunum and ileum. Mod
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Lee JR, Joshi V, Griffin JW et al. Gastrointestinal autonomic nerve tumor. Immunohistochemical and
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