Case 2 -
Multiple Gastrointestinal Stromal Tumors, Histologically Benign, Arising in a Patient with Type 1 Neurofibromatosis
John R. Goldblum
Cleveland Clinic and
Cleveland Clinic Lerner College of Medicine
Cleveland , Ohio
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- 58-year-old male
with multiple neurofibromas, including several plexiform neurofibromas, who presented with a 4 cm small
intestinal mass. He also appeared to have two small, less than 1 cm masses in the wall of the small
bowel several cms away from the main mass. This is a representative section of the 4 cm mass.
Case 2 - Slide 1
Case 2 - Figure 1 - Low-magnification view of the small bowel tumor. The tumor is composed of fairly bland-appearing spindled cells arranged into nests and short intersecting fascicles. Some areas of the tumor showed prominent vascular spaces.
Case 2 - Figure 2 - High-magnification view of bland-appearing spindled cells arranged into a vaguely storiform growth pattern. The cells have abundant eosinophilic fibrillar cytoplasm. Cytologic atypia is not conspicuous.
Case 2 - Figure 3 - High-magnification view of bland spindled cells with conspicuous collagen globules between the cells. Mitotic figures are not seen.
Case 2 - Figure 4 - Separate from the main tumor, there was a grossly inconspicuous but histologically apparent spindle cell proliferation that interdigitated with the surrounding more densely eosinophilic muscle fibers of the muscularis propria.
Case 2 - Figure 5 - Higher magnification view of separate spindle cell proliferation interdigitating among the muscle fibers of the muscularis propria. This spindle cell proliferation is histologically similar to that seen in the other figures from the main tumor.
- strongly CD117-positive; strongly CD34-positive; focal SMA-positive; desmin negative, S100 protein
- Molecular studies - No evidence of KIT or
Multiple gastrointestinal stromal tumors, histologically benign, arising in a
patient with type 1 neurofibromatosis.
Perhaps no other area in surgical pathology has caused as much confusion and controversy as has the
subject of gastrointestinal stromal tumors (GIST). These tumors are a heterogeneous group of neoplasms,
and prediction of clinical behavior requires a multiparametric evaluation of gross and microscopic
features. However, the same criteria for malignancy do not apply to stromal tumors from different sites
within the gastrointestinal tract, and the relative importance of each of these features is somewhat
In the past, cellular spindle cell neoplasms of the gastrointestinal tract have often been referred to
as "leiomyoma" or "leiomyosarcoma" based upon their purported morphologic resemblance to smooth muscle
tumors in other anatomic sites. With the advent of electron microscopy and immunohistochemistry, an
enormous number of publications attempted to analyze the characteristics of the constituent cells of
these tumors. While a number of studies suggested that these tumors were either derived from or
differentiated towards smooth muscle, an equal number of studies suggested neural derivation or
differentiation. As discussed below, more recent evidence suggests that the vast majority (if not all)
of these tumors are either derived from or differentiate toward interstitial cells of Cajal (ICC). The
non-committal term "gastrointestinal stromal tumor" has been adopted to describe this heterogeneous group
of neoplasms and is currently the term of preference. Although a wide array of mesenchymal tumors may
arise within the gastrointestinal tract, GIST are by far the most common mesenchymal tumors of this site.
Molecular Genetic Features of GIST
The recent intense interest in GIST stems from the fact that much has been learned about the molecular
pathogenesis of this heterogeneous group of tumors, and in fact, this tumor serves as the paradigm for
targeted therapy based upon a detectable molecular genetic alteration. Recent studies have established
that activating mutations of the KIT gene are present in up to 95% of GIST and likely play a fundamental
role in the development of these tumors.
Activating mutations of the KIT gene, most
commonly occurring in the juxtamembrane domain in exon 11, result in ligand-independent activation of the
tyrosine kinase activity, and this event appears to be central in the pathogenesis of these tumors. Much
less commonly, mutations in exon 9 (extracellular domain) and exon 13 (kinase domain) can be
Mutations in the KIT gene are not found in other tumors that may potentially be
confused with GIST, including leiomyosarcomas, fibromatoses and peripheral nerve sheath tumors.
The central role of KIT mutations in the pathogenesis of GIST is underscored by the therapeutic
success of the KIT inhibitor, imatinib.
It has been found that most patients with
metastatic GIST show a major clinical response after treatment with this therapeutic agent. In fact, KIT
positivity by immunohistochemistry (CD117) has been considered the gold standard for the diagnosis of
GIST, and, at least for the initial clinical trials, immunoreactivity for this antigen has been used as
an eligibility criterion for Imatinib therapy (discussed further below).
Most recently, however, it has become apparent that not all GIST have mutations in the KIT gene or,
for that matter, stain for CD117. Rather, activating mutations of the platelet derived growth factor
receptor alpha (PDGFRA) gene appears to be an alternative mechanism critical in GIST
In a recent study by Heinrich et al evaluating the genotype of 127
metastatic GIST,  112 cases were found to harbor mutations in the KIT gene (88.2%), including
23 cases with mutations in exon 9 and 85 cases with mutations in exon 11. Six tumors (4.7%) were found
to harbor PDGFRA mutations, none of which harbored mutations in the KIT gene, confirming that these are
mutually exclusive mutational events. Importantly, patients with exon 11 KIT mutations showed a partial
response to imatinib therapy in 83.5%, whereas patients with mutations in exon 9 of the KIT gene and
those who harbored no mutations in either KIT or PDGFRA showed a partial response in 47.8% and 0%,
respectively, suggesting differences in downstream signaling mechanisms which influence the response to
Medeiros and colleagues  studied 25 GIST-like tumors that did not express KIT by
immunohistochemistry (CD117), which accounted for approximately 4% of all of the GIST they evaluated. Of
these 25 CD117-negative GIST-like tumors, 4 tumors harbored mutations in the KIT gene (16%), including 3
with mutations of exon 11 and 1 with an exon 9 mutation. Interestingly, the vast majority of
CD117-negative tumors (18/25; 72%) had detectable mutations in the PDGFRA gene, most commonly in exon 18
(15 of 18 cases). Only 3 of these tumors did not have a mutation in either KIT or PDGFRA. No tumor had
mutations of both KIT and PDGFRA, again confirming that these are mutually exclusive events. This group
of CD117-negative GIST more commonly occurred in males, had a predominant epithelioid morphology and more
commonly arose in extra-gastrointestinal sites, usually the omentum.
Immunohistochemical Features of GIST
The literature on the immunohistochemical features of GIST has evolved over the past 20 years.
Earlier studies focused on the expression of myoid and neural antigens, and the results of these studies
were often conflicting. CD34, a hematopoietic stem cell marker, was found to be expressed in the
majority (approximately 70%) of GIST from all sites.
However, as previously mentioned,
the product of the KIT gene as detected by CD117 is clearly the most sensitive marker of GIST from all
Although some authors have equated immunoreactivity for CD117 as definitional of
GIST, it is clear that not all GIST express this antigen, as shown in the study by Medeiros et
al.  Overall, approximately 95% of GIST express this antigen. As previously mentioned, many
of these CD117-negative GIST harbor mutations in the PDGFRA gene. Thus, Medeiros and colleagues
emphasized that patients with CD117-negative GIST should not necessarily be denied therapy with imatinib.
Myoid markers may be found in a subset of GIST. Up to 20-30% of these tumors stain for smooth muscle
actin, either focally or diffusely; expression of this antigen seems to be reciprocally related to CD34
expression.  Desmin is found in less than 10% of these tumors, and staining is typically
limited to scattered tumor cells with more prominent staining in epithelioid GIST. Heavy caldesmon and
actin-binding cytoskeleton-associated protein are also detected in a subset of these tumors, supporting
at least partial smooth muscle differentiation. 
Neural antigens may also be detected in some of these tumors; S100 protein is found in up to 10% of
GIST, typically with focal immunoreactivity. These tumors are usually negative for neurofilament protein
and GFAP. Finally, although scattered tumor cells may stain for cytokeratins, particularly malignant
epithelioid GIST, the co-expression of CD117 should prevent confusion with a carcinoma.
Prediction of Clinical Behavior of GIST
The prediction of clinical behavior of GIST is notoriously difficult. In fact, the recent article
entitled, "The diagnosis of gastrointestinal stromal tumors: a consensus approach," published in Human Pathology by an esteemed group of pathologists,  states that,
"Criteria for distinguishing benign from malignant GISTs, or at least to identify those lesions more
likely to metastasize, have been sought, analyzed and disputed for many years. Many parameters have been
proposed, but the morphologic features that have gained greatest acceptance as being predictive of
outcome are the mitotic rate and tumor size." In this publication, Fletcher and colleagues proposed an
easy-to-use approach for defining relative risk of aggressive behavior in GIST, utilizing only tumor size
and mitotic counts as parameters. They categorize these tumors as "very low risk," "low risk,"
"intermediate risk" and "high risk," as noted in the table below. Obviously, these authors went to great
lengths to avoid designating a tumor as benign and, conversely, they went to equal lengths to avoid
calling any malignant, opting for "high risk." In the opinion of this author, although this approach has
its appeal given the relative reproducibility of tumor size and mitotic counts as parameters, it is also
believed to be an oversimplification of a complex group of tumors. The major reason for this objection
is that this approach groups GIST from all sites together. In fact, if one gathers experience in
evaluating GIST from different sites, one quickly comes to the conclusion that these tumors are quite
distinct histologically, and numerous clinical studies have shown they are also distinct biologically.
In my opinion, this would be akin to grouping gastric adenocarcinomas with colorectal adenocarcinomas in
a single study evaluating their clinical behavior, something which presumably would never be published.
Although the "Fletcher classification" approach seems reasonable and likely will catch on among
pathologists, the problem still remains that these tumors are quite distinct from one another in
different parts of the gastrointestinal tract. Thus, for the remainder of this discussion, I will admit
my profound bias and provide you with information that I think is important in understanding the
histologic and clinical features of this heterogeneous group of tumors, separated by anatomic site.
Table 1: Proposed Approach for Defining Risk of Aggressive Behavior in GIST
From Fletcher CDM, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a
consensus approach. Hum Pathol 2002;33:459-65.
| ||Tumor Size ||Mitotic Counts|
|Very Low Risk ||<2 cm ||<5/50 HPF|
|Low Risk ||2-5 cm ||<5/50 HPF|
|Intermediate Risk ||<5 cm ||6-10/50 HPF|
| ||5-10 cm ||<5/50 HPF|
|High Risk ||>5 cm ||>5/50 HPF|
| ||>10 cm ||Any mitotic rate|
| ||>Any size ||>10/50 HPF|
Type 1 Neurofibromatosis (NF1) and GIST
The vast majority of GIST are sporadic, but a small percentage arise in patients with NF1. Although
patients with NF1 develop a number of different gastrointestinal and abdominal tumors (e.g. neuromas,
ampullary carcinoid, pheochromocytoma), GIST are thought to be the most common gastrointestinal neoplasm
in these patients.  In recent years, the clinicopathologic and molecular genetic features of
GIST arising in NF1 have been more fully delineated.
Recently, Miettinen and colleagues from the AFIP reported a detailed study of 45 cases of GIST arising
in patients with NF1.  These cases were culled from a review of 3000 patients with GIST
reviewed at the AFIP between 1970 and 1996 (1.6% of GIST). The study included 26 females and 19 males,
whose ages ranged from 23 to 74 years (median 49 years). Most patients presented with gastrointestinal
bleeding and/or anemia, but some presented with intestinal obstruction, a palpable mass on pelvic
examination or as an incidental finding. Most of the tumors arose in the small bowel, but some also
occurred in the stomach. Multiple tumors (usually throughout the small bowel) were found in 28 of 42
patients. Tumor size ranged from 0.4 to up to 29 cm (median 4 cm), and most were smaller than 5 cm.
Histologically, the vast majority of tumors were composed of bland uniform spindled cells arranged in
a vague paraganglioma-like growth pattern. Skeinoid fibers were usually a prominent feature. Most had
low mitotic activity (<5 MF/50HPF), lacked necrosis and mucosal invasion. Only four tumors were
overtly sarcomatous. Interesting, approximately one-half showed ICC hyperplasia in the adjacent
By immunohistochemistry, all (31 of 31) stained for KIT (CD117) and most coexpressed CD34 (23/29).
SMA was detected in 7 of 31 cases, but none expressed desmin. A minority (7 of 19) showed focal staining
for S100 protein.
Molecular analysis revealed wild-type KIT exons 9, 11, 13 and 17 and wild-type PDGFRA exons 12 and 18
in all 16 cases tested.
Clinical follow-up revealed most patients to be alive without disease (20 of 36 patients). Seven
patients died of unrelated causes, 2 died of peri/postoperative complications and 2 were alive with
unknown tumor status. However, 5 patients developed metastatic disease and died as a direct result of
their tumor. Of these, 3 patients had tumors >5 cm, mitotically active (>5 MF/50HPF), or both.
Several other studies have evaluated the molecular features of NF1 related GIST. Kinoshita et
al.  studied 21 GIST in 7 NF1 patients, and none were found to harbor KIT mutation. However,
PDGFRA mutations were not evaluated in this study. In the recent study by Yantiss and
colleagues,  one of 3 NF1 patients had KIT mutations -- this case revealed identical KIT exon
11 point mutations in 3 separate tumors from the same patient. Takazawa et al. found two different KIT
mutations in separate tumors from one patient, and two different PDGFRA mutations in separate tumors from
another patient.  The other 7 patients had neither KIT nor PDGFRA mutations found in their
Clearly, patients with NF1 have an increased risk of developing GIST. Miettinen et al. estimated an
approximately 45-fold increased risk over the general population.  NF1 patients developed
GIST at a younger age than those with sporadic GIST. They are also more likely to develop tumors arising
anywhere in the small bowel when compared to patients with sporadic GIST. There is a slight female
predominance in NF1-related GIST, compared to a slight male predominance in sporadic tumors. Most NF1
patients with GIST have multiple tumors, a feature that is exceedingly uncommon in patients with sporadic
GIST. Usually, the tumors are small, composed of bland spindled cells that are mitotically inactive and
have a favorable clinical outcome. The relatively low frequency of KIT and PDGFRA mutations in
NF1-related GIST suggests a different pathogenesis from sporadic GIST.
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