Contemporary pathology of gastrointestinal stromal tumors.
ABSTRACT Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs harbor a KIT or PDGFRA mutation and express KIT by immunohistochemistry. However, KIT-negative tumors and tumors showing unusual morphologic features can cause major diagnostic problems. The ability to inhibit the active KIT or PDGFRA kinase with tyrosine kinase inhibitors and alternative drugs demands more than ever accurate tumor classification and risk assessment. This article focuses on the pathology of GIST, including unusual variants and morphologic changes resulting from treatment. Parameters for risk assessment, potentially helpful new immunohistochemical markers, differential diagnosis, and the application of molecular classification schemes are discussed.
- SourceAvailable from: Cigdem Usul Afsar[Show abstract] [Hide abstract]
ABSTRACT: Gastrointestinal stromal tumor is the most common mesenchymal neoplasia in the gastrointestinal tract and has a broad spectrum of pathological patterns and also clinical features changing from benign to malignant. Although the well-characterized parameters to predict the outcome have been the size and the mitotic index of the tumor in the patients with early-staged disease, bulky recurrent or metastatic tumor, resistance to medical treatment and mutation analysis are the prognostic factors for advanced stage-GIST. The aim of this study is to investigate new and more practical tissue markers, such as DOG1 and Ki-67 to specify the GIST diagnosis and also to predict the outcome in GIST patients with both localized and advanced staged disease.International Journal of Clinical and Experimental Medicine 01/2014; 7(7):1914-22. · 1.42 Impact Factor
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ABSTRACT: Atonal homolog 1 (Atoh1) is crucial to the differentiation of many cell types and participates in tumorigenesis and progression. However, the expression of Atoh1 in gastrointestinal stromal tumors (GIST) and its relationship to clinical characteristics of this disease remain poorly understood. In this study, immunohistochemical analysis using tissue microarray (TMA) was employed to evaluate the expression of Atoh1 in GIST and the correlation between Atoh1 expression and clinicopathological features of GIST as well as patient outcome. High Atoh1 cytoplasmic expression was observed in 77.22% of patients with GIST, which was related to the mitotic index (P = 0.010) and AFIP-Miettinen risk classification (P = 0.045). High Atoh1 nuclear expression was seen in 69.49% of cases, which was associated with mitotic index (P = 0.003) and AFIP-Miettinen risk classification (P = 0.001). The Kaplan-Meier method and log-rank test indicated that high Atoh1 cytoplasmic expression, high Atoh1 nuclear expression, small tumor diameter, low mitotic index and TNM stage significantly correlated with improved survival of GIST patients. Overall, the data suggest that Atoh1 high expression correlates with a good prognosis and it may serve as a favorable prognostic factor for GIST. These results also support a role for Atoh1 as a tumor suppressor gene in GIST.International journal of clinical and experimental pathology. 01/2014; 7(10):7123-30.
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ABSTRACT: The aim of this study was to investigate the protein expression of DNA methyltransferases (DNMTs, including DNMT1, DNMT2, DNMT3A, DNMT3B and DNMT3L) and methyl-CpG-binding domain protein 2 (MBD2) in gastrointestinal stromal tumor (GIST). Immunohistochemistry and western blot analysis were used to detect expression of DNMT and MBD2 in 15 pairs of adult GIST and matched non-tumor tissues. The protein expression of DNMT1, DNMT2, DNMT3B, DNMT3L and MBD2 was significantly higher in adult GISTs compared to the matched non-tumor tissues (P<0.05). However, no significant difference was detected in the protein expression of DNMT3A between tumor and non-tumor tissues (P>0.05). Associations between DNMT1 expression and mitotic index, DNMT3B expression and tumor size, as well as DNMT3L expression and Helicobacter pylori infection were detected in GISTs (P<0.05). In conclusion, GISTs exhibit a high protein expression of DNMT (with the exception of DNMT3A) and MBD2.Biomedical reports. 01/2013; 1(2):223-227.
Clinical Medicine Insights: Pathology 2012:5 23–33
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R e v I e w
Clinical Medicine Insights: Pathology 2012:5
pathology of Gastrointestinal stromal Tumors
wai Chin Foo1, Bernadette Liegl-Atzwanger2 and Alexander J. Lazar1,3
1Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. 2Institute of
Pathology, Medical University of Graz, Graz, Austria. 3Sarcoma Research Center, The University of Texas M.D. Anderson
Cancer Center, Houston, TX, USA. Corresponding author email: firstname.lastname@example.org
Abstract: Gastrointestinal stromal tumor (GIST) is a well recognized and relatively well understood soft tissue tumor. Early events in
GIST development are activating mutations in KIT or PDGFRA, which occur in most GISTs and encode for mutated tyrosine receptor
kinases that are therapeutic targets for tyrosine kinase inhibitors, including imatinib and sunitinib. A small minority of GISTs possess-
ing neither KIT nor PDGFRA mutations may have germline mutations in SDH, suggesting a potential role of SDH in the pathogenesis.
Immunohistochemical detection of KIT, and more recently DOG1, has proven to be reliable and useful in the diagnosis of GISTs.
Because current and future therapies depend on pathologists, it is important that they recognize KIT-negative GISTs, GISTs in specific
clinical contexts, GISTs with unusual morphology, and GISTs after treatment. This review focuses on recent developments in the under-
standing of the biology, immunohistochemical diagnosis, the role of molecular analysis, and risk assessment of GISTs.
Keywords: GIST, sarcoma, soft tissue, gastrointestinal, molecular analysis, immunohistochemistry
Foo et al
Clinical Medicine Insights: Pathology 2012:5
Gastrointestinal stromal tumors (GISTs) are the most
common mesenchymal tumor of the gastrointestinal
(GI) tract. Prior to their recognition as distinct tumors,
GISTs were most commonly classified as smooth
muscle tumors or neural tumors.1 GISTs are now well
recognized and well understood by pathologists and
clinicians. Our understanding of the biology of these
tumors has expanded significantly since the landmark
work in 1998 by Hirota and colleagues implicating
KIT mutations in the pathogenesis of GISTs, and the
subsequent work in 2003 by Heinrich and colleagues
uncovering activating mutations in platelet-derived
growth factor receptor α (PDGFRA).2,3 The discovery
of these tyrosine kinase receptor mutations in GISTs
and the fortuitous application of the tyrosine kinase
inhibitor (TKI) imatinib mesylate have changed the
therapeutic landscape of this previously treatment-
refractory tumor. The TKI sunitinib has been
approved since 2006 for imatinib-resistant GIST and
other TKIs, as well as other therapies, are under active
clinical investigation. Treatment of GIST is currently
regarded as the paradigm of molecular targeted ther-
apy in solid tumors.
This review provides an overview of recent
advancements in the understanding and diagnosis of
this tumor; in particular, the role of molecular testing
in this era of targeted cancer therapy is discussed.
Historical data concerning the incidence of GIST is
unreliable considering that it was not widely recog-
nized until the late 1990s. Currently, the estimated
annual incidence of clinically relevant GIST in the
United States is set as high as 6,000 cases.4 In one
study examining the Surveillance, Epidemiology,
and End Results (SEER) registry, the incidence is
reported to be 0.32 per 100,000 per year, and the
prevalence is reported to be 1.62 per 100,00 per year
during a 15-year period.5 However, this value may be
an underestimate, as very small GISTs may only be
found incidentally at the time of autopsy or when a
gastrectomy is performed for other reasons. According
to a German and a Japanese study, these micro-GISTs
(1 to 10 mm) can be found in up to 35% of patients
after the age of 50.6,7 These minute GISTs are immu-
noreactive for KIT and often contain an oncogenic
mutation in the KIT or PDGFRA gene.6,8 In a recent
study, the incidence of GISTs examined prospectively
over a two-year period was reported to be higher than
that in the SEER registry, at approximately 1.12 per
100,000 per year. However, this study was confined
to the Rhone-Alpes region in France, which only rep-
resents about 10% of the total French population.9
The true incidence of GIST may be even higher as
diagnostic imaging modalities improve.
GISTs commonly present between the fourth and
eighth decades of life, with a median age of approxi-
mately 60 years.10,11 Much less commonly, GIST can
present in the pediatric population. Overall, there is
no clear sex predilection; however, in specific clini-
cal associations, such as those arising in the pediatric
population, a female predilection has been noted.12–15
The majority of GISTs are sporadic, but GISTs have
been identified in association with neurofibromatosis
type 1 (NF1); Carney triad syndrome characterized
by a constellation of gastric GIST, extra-adrenal para-
ganglioma, and pulmonary chondroma; and Carney-
Stratakis syndrome characterized by a constellation
of gastric GIST and paraganglioma.13,16–23
GISTs most commonly arise in the stomach (60%)
but can be found throughout the GI tract (Fig. 1). The
jejunum and ileum are the second most common site
(30%), followed by the duodenum (5%), colorec-
tum (4%), and esophagus or appendix (,1%).24–30
Jejunum and ileum
Figure 1. Primary GIST anatomic locations and relative frequencies.
Clinical Medicine Insights: Pathology 2012:5
Rarely, they can arise in the omentum, mesentery, or
retroperitoneum, where they are referred to as extra-
gastrointestinal GIST. However, these may represent
large tumors where a connection to the bowel wall was
not formed.31,32 A single case of a primary “GIST” in
the pleura has also been reported recently.33 The major-
ity of GISTs (70%) present with non-specific clinical
symptoms, which vary depending on the size and site
of involvement. The symptoms can include bleed-
ing, perforations, and less commonly, obstruction.11,34
Approximately 20% of cases are asymptomatic and are
found during endoscopy, surgery, or radiologic studies
for other reasons; 10% of cases are detected inciden-
tally at autopsy.11 Overall, metastases are uncommon
and typically only seen in the setting of late-stage
disease with the exception of pediatric GISTs, which
frequently present with lymph node metastases. Other
metastatic sites include the liver, lung, bone, soft tis-
sue, or skin. Metastases are often seen more than
5 years after the initial surgery.35–37
Pediatric gastrointestinal stromal
Pediatric GISTs represent 1%–2% of all GISTs and
occur most commonly in the second decade of life,
with a predilection in females. These tumors arise
almost exclusively in the stomach and frequently
involve the lymph nodes. Only 10%–15% of these
GISTs harbor KIT or PDGFRA mutations and, thus,
the majority of these GISTs fall under the broad rubric
of so-called “wild-type” GIST.12–15
“wild-type” gastrointestinal stromal
Wild-type GISTs are seen primarily in children
(approximately 85%–90%)12–15 and in a small per-
centage of adults (10%–15%)34 and are characterized
by the lack of KIT and PDGFRA mutations. Conse-
quently, standard GIST therapies (ie, imatinib and
sunitinib) are less efficacious in this clinical group.
Although the pathogenesis is largely unknown, recent
studies have uncovered germline mutations involving
succinate dehydrogenase (SDH), most commonly in
the subunit genes SDHB and SDHC, resulting in a
complete loss or reduction in SDH protein.12,13 Loss
of SDH protein expression is effectively demon-
strated using traditional immunohistochemistry.13,19,38
The clinical features associated with the presence of
SDH germline mutations in wild-type GISTs, which
accounted for 12% of wild-type GISTs in one study,
has not been defined.13 In adult wild-type-GISTs,
BRAF exon 15 V600E mutations have been detected
in 7%–13% of GISTs, commonly located in the small
Gastrointestinal stromal tumors
in association with Carney’s triad
GISTs are one of the characteristic tumor types found
in Carney’s triad and Carney-Stratakis. This clinical
subtype has unique clinical features compared with
their sporadic counterparts, including occurrence at
a younger age, a female gender predilection, multi-
focality, slow growth, frequent metastases (similar to
pediatric GISTs), lack of response to imatinib treat-
ment, and, infrequently, a fatal outcome. This tumor
commonly presents in the gastric antrum and does
not harbor KIT or PDGFRA mutations. Interestingly,
there is no correlation between conventional risk
assessment and tumor behavior; even with metastatic
disease, clinical behavior is unpredictable, with many
cases having a relatively favorable outcome regard-
less of clinical stage.22,23,41,42
Neurofibromatosis type 1 associated
gastrointestinal stromal tumors
GISTs arising in patients with NF1 typically present
with multiple tumors involving the small bowel. The
majority of these tumors are mitotically inactive and
clinically benign. However, clinically malignant GISTs
can arise in these patients. Whether or not these GISTs
arise sporadically or represent malignant transforma-
tion from a benign tumor is unclear. Interestingly,
these tumors generally do not harbor either KIT or
PDGFRA mutations. The characteristic loss of neuro-
fibromin function (encoded by the NF1 gene) allows
hyperactivity of the RAS proto- oncogene, which
is downstream of KIT and likely plays a role in the
pathogenesis of this tumor.16,21,43
GISTs are well-circumscribed tumors most com-
monly arising in the muscularis propria of the GI
tract. The tumor size varies; for high-risk GIST, the
Foo et al
Clinical Medicine Insights: Pathology 2012:5
median tumor size is 8.9 cm.44 These tumors have
a fleshy pink or tan-white cut surface with hemor-
rhagic foci, central cystic degenerative changes, or
GISTs are monotonous tumors that can be divided
into three principal subtypes depending on the
morphology. The majority of GISTs (approximately
70% of cases) are composed of spindle cells with
palely eosinophilic fibrillary cytoplasm, ovoid nuclei,
and syncytial cell borders. Paranuclear vacuoliza-
tion is frequently seen (Fig. 2A and B). Extracellu-
lar deposits of dense, collagen (skeinoid fibers) are
also seen (Fig. 2C). The cells are arranged in short
fascicles or whorls. NF1-associated GISTs seem to
invariably show this morphology.16 About 20% of
cases are composed of epithelioid cells with palely
eosinophilic to clear cytoplasms and round nuclei.
The cells are arranged in nests, sheets, and, less com-
monly, cords (Fig. 2D). This morphology is com-
monly seen in pediatric GISTs.12,20 The remaining
10% of GISTs have a mixed spindle and epithelioid
cell morphology. Regardless of the cytomorphology,
GISTs are variably cellular and can have sclerotic,
collagenous, or myxoid stromal changes. Pleomor-
phism can be seen very occasionally.
Figure 2. GIST subtypes and morphology. (A) GIST composed of spindle
cells with paley eosinophilic, fibrillary cytoplasm with focal paranuclear
vacuolization, H&e 200X. (B) GIST showing more prominent paranu-
clear vacuolization, H&e 200X. (c) GIST with spindle cells and extracel-
lular skeinoid fibers, H&E 200X. (D) GIST composed of epithelioid cells
with eosinophilic and clear cytoplasm, H&e 200X.
Figure 3. GIST after treatment with tyrosine kinase inhibitors. (A) GIST
with decreased cellularity and hyalinized areas, H&e 40X. (B) KIT immu-
nohistochemical staining can be useful in highlighting residual neoplastic
After treatment with TKIs, responsive GISTs may
show dramatically decreased cellularity and stromal
changes, including marked hyalinization and myxoid
features (Fig. 3).45 Other described post-treatment
findings include: loss of KIT expression; a change
from spindle to purely epithelioid cell morphology;
a pseudopapillary epithelioid growth pattern; and,
rarely, rhabdomyosarcomatous differentiation.46,47
These changes can create diagnostic challenges for
the unaware pathologist.
Oncogenic KIT and PDGFRA mutations
KIT and PDGFRA genes both encode structurally
similar tyrosine kinase receptors. These receptors are
composed of an extracellular ligand-binding region, a
transmembrane sequence, a juxtamembrane domain,
and two cytoplasmic kinase domains. In GISTs,
mutations in KIT and PDGFRA result in expressed
proteins with constitutive oncogenic signaling in the
absence of their ligands. The uncontrolled kinase
activity results in alterations to cell cycle, protein
translation, metabolism, and apoptosis.48,49 KIT and
PDGFRA mutations are mutually exclusive.
In GISTs, mutations in KIT and PDGFRA genes
generally involve either the cytoplasmic kinase domain
or the juxtamembrane (intracellular or extracellular)
regions (Fig. 4). The vast majority of KIT mutations
are juxtamembrane and found in exon 11 (∼70%) and
in exon 9 (∼10%).3,18 The former consists of variables,
deletions, point mutations, and insertions that can
involve virtually any portion of the exon; although
hot spots do exist with the latter, these almost invari-
ably represent a characteristic duplication of amino
acids 502 and 503. Both mutations result in ligand-
independent kinase activation. GISTs with KIT exon
11 mutations can occur throughout the GI tract whereas
Clinical Medicine Insights: Pathology 2012:5
been reported in other mesenchymal tumors, including
smooth muscle neoplasms and synovial sarcomas.57,60–65
CD34 was an early marker for GIST and is com-
monly used in the immunohistochemical workup for
spindle cell tumors in the GI tract (Fig. 5C). It is less
sensitive and specific than either KIT or DOG1, with
rates of expression varying from 50%–90% depend-
ing on tumor site.26 In addition to GISTs, CD34 immu-
noreactivity has been reported in other mesenchymal
tumors, including leiomyosarcoma and others that
may enter into the differential diagnosis of GISTs.58
Antibodies to PDGFRA, a tyrosine kinase recep-
tor closely related to KIT, can be employed in cases
of KIT-negative GISTs harboring a mutation in
PDGFRA. Strong immunoreactivity can be found
most commonly in epithelioid GISTs. Its utility is pri-
marily limited by the reports of inconsistent immu-
nohistochemical results when using commercially
available antibodies. In addition, immunoreactivity has
also been described in other mesenchymal tumors.66,67
Other commonly used markers include caldes-
mon, smooth muscle actin, desmin, S-100 protein,
and keratin, which can be variably immunoreactive
in GISTs (Table 1). Notably, caldesmon immunoreac-
tivity is seen in over two-thirds of GISTs;31,58 smooth
muscle actin immunoreactivity is seen in less than
one-third of GISTs. S-100 protein, cytokeratins, and
desmin immunoreactivity are seen significantly less.58
Fortunately, significant degrees of desmin and S-100
protein reactivity are rare since these raise the diag-
nostic issue of smooth muscle tumor and nerve sheath
neoplasm or melanoma, respectively, and can be con-
fusing, particularly in small biopsies.
Clinical history, traditional microscopy, and immu-
nohistochemistry are usually sufficient to establish
the diagnosis of GIST. However, in tumors where the
diagnosis remains uncertain, real-time polymerase
chain reaction (RT-PCR) testing for KIT or PDGFRA
gene mutations may be useful. A number of academic
centers offer this type of testing, as do private refer-
In what is more likely to be the future role of molec-
ular testing in GISTs, there has been an increasing
trend, primarily at large cancer treatment centers, to
employ routine testing for specific mutations to guide
initial tumor management. This trend has largely been
Exon 9 (~10%)
Exon 11 (~70%)
Exon 13 (~1%)
Exon 17 (~1%)
Exon 12 (~1%)
Exon 18 (~5%)
Exon 14 (~1%)
Figure 4. Diagram of KIT and PDGFRA receptor tyrosine kinases with
location and relative frequencies of mutations.
KIT exon 9 mutants occur most frequently in the small
bowel.4,26,50,51 Rarely, there are point mutations in exon
13 and 17, both of which encode a portion of the
kinase domain and lead to kinase activation. GISTs
harboring these mutations are very uncommon, but
usually arise in the small intestine.52 PDGFRA muta-
tions represent a minority of the overall GISTs (less
than 10%) and primarily either exon 18 or exon 14.53
PDGFRA mutant GISTs are generally limited to the
stomach, predominantly epithelioid in morphology,
and clinically less aggressive.53,54
KIT expression is a specific and sensitive marker for
GIST within the standard differential diagnostic set-
ting (Table 1). Over 90% of GISTs are immunoreac-
tive for KIT.34 Most GISTs show a strong and diffuse
cytoplasmic staining for KIT; a minority of GISTs can
also exhibit a dot-like or membranous staining pattern
(Fig. 5A).2,55–58 The extent and pattern of KIT immuno-
reactivity has no impact on the likelihood of treatment
response.59 While other neoplasms, such as a subset
of melanomas, can also show expression of KIT, an
appropriate panel of immunohistochemical stains will
avoid diagnostic errors in the vast majority of cases.58
Discovered on GIST1 (DOG1) is a promising new
marker (Fig. 5B), which has proven in early studies
to be a sensitive and specific marker for GISTs.57,60–65
It is immunoreactive in pediatric GISTs and NF1-
associated GISTs. Notably, DOG1 stains about one-
third of KIT-negative GISTs.62 Given that up to 5% of
GISTs do not express KIT, this marker is especially
useful for diagnosis. Rare DOG1 immunoreactivity has
Foo et al
Clinical Medicine Insights: Pathology 2012:5
driven by phase II–III results of clinical trials that
show that response to imatinib may be dependent on
the specific KIT mutation. Some PDGFRA mutant
GISTs show at least partial response to imatinib; how-
ever, the most common PDGFRA mutation in GISTs
(D842V) confers a complete resistance to the drug.54,68
In KIT mutant GISTs, a mutation in exon 11 was asso-
ciated with a higher response rate (67%–83%) than a
mutation in exon 9 (35%–48%). Conversely, primary
resistance to imatinib was also associated with the spe-
cific KIT mutation, in particular primary point muta-
tions in exons 13 and 17. KIT exon 11 mutant GISTs
were the least likely (0%–5%) to show primary resis-
tance. GISTs with neither KIT nor PDGFRA muta-
tions showed the least treatment response (0%–39%)
and the highest primary resistance (23%) to imatinib.
Despite these trends, sometimes GISTs with identical
mutations in KIT will respond differently to imatinib.
Explanations for this are unclear, but may involve
variable plasma levels of imatinib between patients
and perhaps additional mutations in other genes. Most
of the well-validated data for genotype-response cor-
relations is based on imatinib, which is the first-line
treatment for GIST; however, it is clear that other
members of the ever increasing family of TKIs that
target KIT, PDGFRA, and other receptors will have
differing efficacies for various mutation types.34,44,69–71
Whereas initially the great majority of GISTs
are often highly responsive to treatment with TKIs,
acquired resistance is a vexing problem affecting the
majority of patients. Mechanisms of resistance most
commonly include secondary (acquired) mutations
in the KIT kinase domain and rarely KIT/PDGFRA
genomic amplifications or activation of alternative
oncogenes.3,68,72 Secondary KIT mutations are most
Table 1. Immunohistochemistry and molecular findings of GISTs and its differential diagnosis.
cD34sMAcALDesDes s-100 Other
KIT mut.; PDFGRA mut.;
SDHB and SDHC mut.
Solitary fibrous tumors
CTNNB1 mut.; germline
2p23 and ALK rearrang.
Abbreviations: CALDES, caldesmon; CHR, chromogranin; DES, desmin; GFAP, glial fibrillary acidic protein; MPNST, malignant peripheral nerve sheath
tumor; SMA, smooth muscle actin; SYN, synaptophysin.
Table data is aggregated from references.2,24,29,35,53–56,58–65
Figure 5. GIST showing positive membranous immunoreactivity for
(A) KIT, 200X; (B) DOG1, 200X; and (c) CD34, 200X.
Clinical Medicine Insights: Pathology 2012:5
commonly single nucleotide substitutions affecting
codons in the ATP binding pocket (exons 13 and 14)
and the kinase activation loop (exons 17 and 18).
These secondary mutations can be detected in up to
83% of patients.69,73 Recent in vitro and in vivo studies
demonstrated that sunitinib, a TKI used after imatinib
failure, is only effective against secondary mutations
located in the ATP binding pocket but not against sec-
ondary mutations in the kinase activation loop.74,75
Liegl et al recently demonstrated the substantial
inter- and intra-lesional heterogeneity in TKI-resistant
mutations in patients treated with imatinib alone or
imatinib and sunitinib. In 67% of patients, 2–5 dif-
ferent secondary mutations were detected in separate
metastases, and in 34% of patients, two secondary KIT
mutations were even seen within a single metastasis.72
These findings emphasize that testing of secondary
KIT resistance mutations in a biopsy specimen will not
aid in demonstrating the whole spectrum of resistance
mutations. Thus, there are currently no clear recom-
mendations and indications for resistance testing.
Currently, there are no established guidelines for
routine KIT or PDGFRA mutational testing. Irrespec-
tive of their mutational status, most GISTs are treated
with imatinib as first-line therapy; however, this may
change in the future. The National Comprehensive
Cancer Network (NCCN) and European Organisa-
tion for Research and Treatment of Cancer (EORTC)
suggest obtaining mutational testing in GISTs that
are unresectable or metastatic at presentation, are in
young patients, have epithelioid morphology, and
have primary resistance to imatinib. Recent prospec-
tive clinical trial data shows that patients with KIT
exon 9 mutations respond more poorly than those
with exon 11 mutations to 400 mg of daily oral ima-
tinib, but that this difference in response is amelio-
rated when exon 9 mutant patients receive 800 mg
imatinib daily. This higher dose generally does not
improve response for the standard, imatinib-sensitive
exon 11 mutations.68 This type of data argues strongly
for the relevance of genotyping; although, it is cur-
rently not known whether genotyping up front to
allow immediate higher dosing offers advantages over
dose escalation with initial resistance, as has been the
current practice. As our understanding of the relation-
ship between genotype and response to various TKIs
increases, genotyping will likely become increasingly
relevant for therapeutic selection.
The differential diagnosis of GISTs is influenced by
the morphology of the tumor. Both epithelial and other
mesenchymal tumors enter into the differential diagnosis.
Spindle cell morphology
The differential diagnosis for spindle cell GISTs con-
sists primarily of other mesenchymal tumors, including
leiomyomas, leiomyosarcomas, intra-abdominal des-
moid fibromatoses, schwannomas, inflammatory myo-
fibroblastic tumors, and solitary fibrous tumors.76
Leiomyomas and leiomyosarcomas are the most
likely to be confused with GISTs. These smooth mus-
cle tumors are composed of spindle cells with sausage-
shaped nuclei, brightly eosinophilic cytoplasm, and
distinct cell borders. In contrast, spindle cell GISTs
have more ovoid nuclei and have a more syncytial
appearance. All 3 tumors can be immunoreactive for
smooth muscle actin and caldesmon. Although desmin
positivity is rarely seen in GISTs (around 1%–2%), it
is much more common in leiomyomas and leiomyo-
sarcomas (greater than 90%–95%).58,76
Intra-abdominal desmoid fibromatoses are composed
of myofibroblastic cells set in an eosinophilic collag-
enous matrix and arranged in long sweeping fascicles.
These tumors can be positive for smooth muscle actin
and, infrequently, KIT;77 immunohistochemistry dem-
onstrates strong nuclear staining for β-catenin in 70%
of cases.78–80 Ancillary testing for CTNNB1 or APC gene
mutations can also be employed.81
Inflammatory myofibroblastic tumors (IMTs) are
composed of atypical myofibroblastic cells arranged
in fascicles and admixed with a prominent lymphop-
lasmacytic infiltrate. In contrast to GISTs, the spindle
cells have more vesicular tapering nuclei and more
well-defined cell borders. IMTs are immunoreactive
to both smooth muscle actin and desmin. In addition,
ALK-1 immunoreactivity and ALK gene rearrange-
ment can be seen in a subset of these tumors.82,83
Schwannomas in the GI tract are composed of
bland spindle cells with wavy nuclei and fibrillary
cytoplasm. The tumor is typically surrounded by a cuff
of lymphocytes and diffusely expresses S-100 protein
and glial fibrillary acidic protein (GFAP).84,85 Soli-
tary fibrous tumors are also composed of bland spin-
dle cells, but these are arranged in characteristically
pattern-less architecture with stag horn vessels. The
cells have scant cytoplasm and short, stubby nuclei.
Foo et al
Clinical Medicine Insights: Pathology 2012:5
Table 2. Risk stratification of primary GISTs based on mitotic index, tumor size, and anatomic site.*
Mitotic Indexsize, cm Risk of progressive disease (%)
Gastric Duodenum Jejunum/ileumRectum
#5 per 50 HPF
.2 to #5
.5 to #10
.2 to #5
.5 to #10
very low (1.9)
.5 per 50 HPF
*Adapted from Miettinen M, Lasota RJ. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70–83,
with permission from elsevier; †denotes small number of cases.
Abbreviations: GIST, gastrointestinal stromal tumor; HPF, high-power field.
Both GISTs and solitary fibrous tumors can express
CD34.56,58,76 However, KIT or DOG1 expression has
not been reported in these tumors.65
The differential diagnosis for epithelioid GISTs
includes both carcinomas, such as neuroendocrine
carcinomas and other mesenchymal neoplasms, such
as clear cell sarcomas. Neuroendocrine carcinomas
are characterized by cytokeratin, synaptophysin,
and chromogranin positivity. Clear cell sarcoma, of
which a subset occurs as a primary GI tract tumor,
expresses S-100 protein and second-line melanoma
markers, such as HMB-45 or melan A, and are
also characterized by EWSR1-CREB1 or -ATF1 gene
predictors of clinical Behavior
Risk assessment in gastrointestinal
Because the assessment of GIST recurrence risk is
currently based on morphology, the pathologist has
an important role in the clinical management and
optimal care of GIST patients. Numerous studies have
shown that mitotic activity and tumor size are highly
prognostic of the risk of aggressive primary tumors.1
These two parameters served as the initial foundation
for the consensus approach for risk assessment in
GIST. Subsequent studies have added a third parame-
ter, anatomic location, as the next strongest and useful
prognosticator. Miettinen and colleagues have shown
that small intestinal and rectal GISTs were generally
more aggressive than those in the stomach (Table 2).
Based on these studies, the 2007 and 2010 NCCN and
EORTC guidelines recommend that risk assessment
for GISTs be determined by tumor size, anatomic
site, and mitotic activity in order to determine which
patients will receive adjuvant TKI therapy.34,88,89
Tumor rupture is also associated with an increased
risk of recurrence.90–93 However, whether or not tumor
rupture is an independent prognostic factor is contro-
versial. Joensuu et al and Rutkowski et al both found
that ruptured tumors exhibited more aggressive fea-
tures; (ie, larger size, increased mitotic figures, and
Although GIST is now a well-recognized entity,
the pathologist must be aware of the wide morpho-
logic spectrum of GISTs, including the common
morphologic subgroups, the unusual morphologic
variants, and the morphologic changes that may be
encountered after treatment. Despite these differ-
ences in morphology, however, almost all cases can
be assessed for risk stratification using the 2007 and
2010 NCCN guidelines along with those from the
EORTC, which include mitotic activity, tumor size,
and tumor location. In light of the morphologic spec-
trum, immunohistochemistry for KIT and CD34
among others is exceedingly useful in distinguishing
GISTs from their morphologic mimics. Promising
new immunohistochemical markers, such as DOG1,
will likely be diagnostically valuable, especially in
GISTs lacking KIT expression. Currently, there is no
standard of care requiring routine molecular testing in
situations other than confirmation of the diagnosis in
Clinical Medicine Insights: Pathology 2012:5
KIT-negative or DOG1-negative cases. However, in
the future, molecular testing may become common-
place for guiding initial treatment. It is also likely that
the treatment of GIST will evolve toward the simul-
taneous use of multiple TKIs and perhaps agents that
act through other mechanisms in order to avoid the
emergence of resistance.
Analysed the data: WCF, BLA, AJL. Wrote the first
draft of the manuscript: WCF. Contributed to the writ-
ing of the manuscript: WCF, BLA, AJL. Agree with
manuscript results and conclusions: WCF, BLA, AJL.
Jointly developed the structure and arguments for the
paper: WCF, BLA, AJL. Made critical revisions and
approved final version: WCF, BLA, AJL. All authors
reviewed and approved of the final manuscript.
Financial support for medical editorial assistance was
provided by Novartis Pharmaceuticals, who reviewed
the manuscript for medical accuracy only. We thank
Simon J. Slater, PhD, and Jennifer L. Giel, PhD, CMPP,
formerly and currently of Evidence Scientific Solu-
tions, part of the UBC-Envision Group, Philadelphia,
PA, respectively, for their medical editorial assistance
with this manuscript.
Wai Chin Foo, MD: None. Bernadette Liegl-
Atzwanger, MD: None. Alexander J. Lazar, MD,
PhD: Novartis, Pfizer, GlaxoSmithKline, Roche, and
Disclosures and ethics
As a requirement of publication author(s) have pro-
vided to the publisher signed confirmation of compli-
ance with legal and ethical obligations including but
not limited to the following: authorship and contribu-
torship, conflicts of interest, privacy and confidential-
ity and (where applicable) protection of human and
animal research subjects. The authors have read and
confirmed their agreement with the ICMJE author-
ship and conflict of interest criteria. The authors have
also confirmed that this article is unique and not under
consideration or published in any other publication,
and that they have permission from rights holders to
reproduce any copyrighted material. Any disclosures
are made in this section. The external blind peer
reviewers report no conflicts of interest.
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