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23 Epidemiology, Pathology, Diagnosis,
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Prevention, and Management of GI
Stromal Tumors and Other GI Sarcomas
Andrea Napolitano, Myles J. Smith, Charlotte Benson & Robin L. Jones
Institute for Cancer Research, Royal Marsden Hospital, London, UK
[Aspects of disease affecting the small bowel are covered in Chapter 8].
Gastrointestinal Stromal Tumors (GIST)
Introduction and Nomenclature
Gastrointestinal stromal tumors (GIST) are a heterogeneous
group of mesenchymal tumors of the gastrointestinal (GI) tract
with variable clinical behavior (from benign to overtly malignant) believed to arise in most cases from the interstitial cells of
Cajal (ICC) or their multipotential precursor cells. ICC are
spindle cells with pacemaker activity, which regulate autonomous nerve transmission and intestinal peristalsis (Corless
et al. 2011).
GIST can occur throughout the GI tract, most frequently in
the stomach (55–60%) and the small intestine (25–30%), and
significantly more rarely in the colon-rectum (4–6%) and distal
esophagus (<1%). Small numbers of GIST have been reported
as primary tumors in the omentum, mesentery, retroperitoneum and in extra-GI locations. From a molecular perspective,
GIST are characterized by the presence of usually mutually
exclusive activating mutations in the receptor tyrosine kinase
(RTK) KIT and PDGFRA genes, which can be found in ~80% of
all GIST cases. Although molecular analysis are becoming
increasingly important in the management of GIST patients,
the initial diagnosis is usually histologic: GIST can present with
spindle or epithelioid morphology, and generally express the
immunohistochemical markers CD117 (KIT) and/or DOG1
(encoded by ANO1) (Blay et al. 2021).
GIST <2 cm in size, termed micro-GIST (<1 cm) or miniGIST (1–2 cm), are considered putative precursor lesions of
larger GIST and are often incidentally discovered. They are generally not resected, as they carry a relatively low individual risk
of progression, whereas larger resectable GIST can be cured
with surgery. After the discovery of druggable driver mutations,
advanced GIST have represented a prototypical solid tumor
wherein targeted therapies have proven significantly more
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
effective than conventional chemotherapy. In fact, unresectable
and metastatic GIST are in almost all cases treated with tyrosine
kinase inhibitors (TKI) that target KIT and/or PDGFRα. In
particular, the TKI imatinib represents the first-line treatment
for most advanced GIST patients as well as the adjuvant
treatment for patients with resected disease at high risk of
relapse. Secondary mutations acquired during treatment can
cause drug resistance, thus partially limiting treatment success
(Casali et al. 2022).
In the past, GIST were classified as GI smooth muscle tumors
and GI autonomic nerve or nerve sheath tumors. It is nowadays
clear from genetic and immunohistochemical analyses that
GIST comprise more than 80% of all mesenchymal tumors of
the GI tract, and they include the large majority of tumors previously classified as GI leiomyomas and leiomyosarcomas
(Lasota et al. 1999; Lee et al. 2001). Nevertheless, it should be
noted that other sarcomas, in particular leiomyosarcomas, can
be found in the GI tract and these will be separately covered in
the second part of this chapter.
Epidemiology
GIST occur with an estimated incidence of 6–22 per million
individuals per year, with differences between geographical
areas and over time. The apparent incidence of diagnosed cases
might depend on factors such as healthcare availability, number
of endoscopic and surgical procedures that give an opportunity
to detect incidental GIST, and on true variation in GIST
population incidence (Ma et al. 2015; Soreide et al. 2016).
Median age at GIST diagnosis varies between 60 and 65
years, with only 10% of all GIST patients diagnosed before the
age of 40 years and less than 1% diagnosed before the age of 18
years. GIST in the adult population are equally distributed between genders, usually present with somatic mutations in KIT
or PDGFRA, and are for the vast majority sporadic in nature
(Blay et al. 2021). GIST occurring in children and young adults
are more commonly diagnosed in females and in the gastric
location, are often lacking driver KIT or PDGFRA mutations
(collectively termed KIT/ PDGFRA wild-type GIST) and can
457
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be found as part of specific tumor syndromes. Of these, neurofibromatosis 1 (NF1) is the most common, followed by syndromes associated to inactivation of the mitochondrial tumor
suppressor gene pathway of the succinate dehydrogenase
(SDH) (i.e. the Carney–Stratakis syndrome and the Carney
triad), and multifocal familial GIST with inheritable KIT or
PDGFRA mutations (Boikos et al. 2016).
Clinical Presentation and Natural History
The clinical presentation of GIST is the classical presentation of a tumor of the digestive tract, with the most common
symptoms being gastrointestinal bleeding, weight loss, and
abdominal pain. Importantly, about one third of all GIST
is incidentally diagnosed in asymptomatic patients during
gastroscopy, abdominal surgery, or radiologic exams performed for an unrelated condition, or by routine clinical
examination.
Bleeding results from an ulcerated tumor and it is more commonly insidious and occult, resulting in chronic anemia and
associated symptoms. More rarely, acute bleeding manifests as
melena, and can lead to a medical emergency. Larger esophageal, intestinal, and rectal GIST can cause symptomatic
obstruction, while intussusception is a rare complication.
Larger cystic tumors may rupture into the abdominal cavity
and cause an acute abdomen. Some patients with larger
necrotic, possibly secondarily infected tumors, may have generalized infection-like symptoms such as fever, usually
combined with abdominal pain. In advanced cases, signs and
symptoms might depend on the presence of metastatic
disease.
Metastases more commonly develop in GIST with higher
mitotic activity, typically within 1–2 years from presentation,
often even after apparently complete surgery. Tumours with
lower mitotic activity and smaller dimensions metastasize less
frequently, and this may often be after a considerable delay that
can be of 10 years or more after surgery. Risk assessment in
localized resected GIST has been evaluated with several
classifications over the years and will discussed in a separate
paragraph.
Common metastatic sites for GISTs are the omentum, the
mesentery, and the other peritoneal surfaces. For this reason,
primary or metastatic GIST can often simulate a gynecologic
cancer. Liver metastases are also common for GIST of any
origin, and the involvement varies from solitary or multiple
nodules to diffuse involvement in advanced cases. Lung metastases are exceptionally rare in GIST, in contrast to other types of
soft tissue sarcomas. Also, histologically verifiable lymph node
metastases are extremely rare. Bone metastases (especially the
axial skeleton) and peripheral soft tissue metastases can also
rarely occur. The soft tissue of abdominal wall represents an
exception, as it is affected more frequently.
Diagnosis
The strategy to carry out a diagnostic biopsy for morphologic
and molecular diagnosis depends on the location and size of
the tumor and clinical circumstances. Tumors that ulcerate gastrointestinal mucosa can often be reached via endoscopic
biopsy, except when in the jejunum or ileum. Gastric tumors
located beyond the mucosa can be reached via ultrasoundguided endoscopic biopsy. Ultrasound or CT-guided biopsies
are used for larger abdominal tumors or for metastatic lesions.
Importantly, percutaneous biopsies have not been associated to
a significant risk of dissemination or relapse. Smaller tumors
that are tentatively identified as GIST are definitively diagnosed
in the excision specimen. Saving multiple samples of tissue in a
tumor bank should be considered whenever possible, because
this will facilitate subsequent molecular analysis (Blay et al.
2021; Casali et al. 2022).
Staging procedures for GIST patients usually include contrast-enhanced computed tomography (CT) scan of the
abdomen and pelvis. Magnetic resonance imaging (MRI) may
be an alternative procedure, especially for rectal GIST, and
(Choi et al.) 2-fluoro-2-deoxy-D-glucose positron emission
tomography (FDG-PET) may be useful when early evaluation
of the tumor response to treatment is useful. Radiologically,
the most common imaging appearance of primary GIST is a
mass arising from the gastrointestinal wall and projecting into
the abdominal cavity. Less commonly, GISTs are intramural
masses or intraluminal polyps. In all morphologies, GIST typically have smoothly marginated outer contours. As they
enlarge, focal ulceration may occur on the mucosal surface
overlying the tumor. Small GIST are typically homogeneous
on imaging studies. In contrast, larger GIST are more commonly heterogeneous on imaging studies because of degenerative, necrotic, and hemorrhagic regions within the tumor
(King 2005).
Histologically, GIST can be relatively reliably identified by
their characteristic morphologic features by an experienced
pathologist. Approximately 70% of GIST are spindle cell tumors,
consisting of cells with fibrillary cytoplasm and ovoid nuclei;
~20% has epithelioid morphology, with rounded cells and occasional focal pleomorphism; the remaining 10% has a mixed
phenotype. The morphology is partially dependent on the
tumor location as well, with intestinal GIST being in the vast
majority of cases spindle cell tumors. The diagnosis of GIST is
usually confirmed by the immunohistochemical demonstration
of CD117 (KIT) positivity. Detection of CD117 positivity in
mast cells and ICC and its absence in normal smooth muscle
and fibroblasts serve as excellent internal controls to validate the
sensitivity and specificity of KIT immunostaining. CD117 is
absent in most other tumors considered in the differential diagnosis of GIST; however, it should be considered that melanoma,
mastocytoma, Ewing sarcoma, and angiosarcoma are among
23 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF GI STROMAL TUMORS 459
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non-GISTs that can be KIT-positive. Additional immunohistochemical markers, such as DOG1 (positive in ~90–95% of all
cases) and CD34 (positive in ~70% of all cases), are also often
used. These markers are particularly important in some
PDGFRA mutant and KIT/PDGRA wild-type GIST, wherein
CD117 positivity can be weak or absent altogether. Finally,
mutational analysis can further confirm the diagnosis of GIST
and simultaneously provide useful information for treatment
selection (Espinosa et al. 2008; Miettinen et al. 2000).
Pathophysiology and Molecular Subgroups
of GIST
The etiology and pathophysiology of GIST are poorly understood, with no clear environmental risk factor contributing to
the development of the disease. As KIT and PDGFRA mutations are also found in small benign micro- and mini-GIST,
they likely represent early pathogenic events that are necessary
although not sufficient for the full malignant transformation of
ICC (Blay et al. 2021).
Additional genomic evets contributing to the transformation
in malignant GIST include loss or inactivation of several cell
cycle regulators as well as of the tumor suppressors MAX and
DPDC5 (Heinrich et al. 2019; Pang et al. 2019; Schaefer et al.
2017). Other downstream events crucially important in the
pathogenesis of GIST are considered to be the overexpression
of the transcription factor ETV1 and the upregulation of the
MEK-MAPK and PI3K pathways (Bosbach et al. 2017; Chi
et al. 2010).
As already anticipated, mutually exclusive molecular driver
events can be identified in more than 95% of all GIST cases.
These alterations define subgroups of GIST with diverging and
overlapping pathologic, biological, and clinical characteristics.
The largest group is represented by GIST harboring KIT and
PDGFRA mutations, respectively found in 60–70% and 10–15%
of all GIST patients. The mutations cause changes in the amino
acid sequence of the KIT or PDGFRα proteins by substituting
one amino acid for another, or by deleting or adding new amino
acid residues. The mutant proteins are presumed to abnormally
activate the KIT and PDGFRα signal transduction pathway,
which under normal circumstances is activated by growth
factor signals. Because sensitivity to targeted kinase inhibitor
treatment (especially for imatinib) depends on KIT or PDGFRA
mutation type, mutation analysis is helpful in tailoring the
therapy for individual patients. Also, detection of GIST-specific
KIT or PDGFRA mutations is useful in verifying the diagnosis
in cases that are negative for CD117 expression.
The remaining KIT/PDGFRA wild-type GIST include those
carrying genetic or epigenetic alterations in SDH family genes
(~10% of all GIST), and those significantly rarer with alterations in RAS family genes (e.g. NF1 and BRAF) or gene fusions
(Figure 1). The main characteristics of each molecular subtype
will be summarized below (Boikos et al. 2016).
Figure 1 Frequency of the different molecular subgroups of GIST.
KIT
KIT is a transmembrane tyrosine kinase receptor structurally
related to the colony stimulating factor 1 receptor and PDGFRs,
with kinase activity induced following dimerization upon
binding of its ligand, stem cell factor (SCF). From a structural
perspective, KIT is characterized by the presence of an extracellular domain responsible of ligand binding and receptor
dimerization (encoded in exons 1 to 9); a single transmembrane helix (exon 10); a cytosolic juxtamembrane domain with
autoinhibitory function (exon 11); and a cytoplasmic kinase
domain split in an ATP-binding domain (including exons 13
and 14) and an activation loop domain (including exons 17 and
18) (Lennartsson and Ronnstrand 2012).
KIT mutations are found in 60–70% of all GIST patients and
include in frame deletions, deletions-insertions and insertions,
and point mutations. About 85% of all primary KIT mutations
are found in exon 11, with approximately half of these mutations represented by deletions of the KIT codons 557–558. The
next most frequent primary mutation is the duplication insertion of codons 502–503 in exon 9, responsible of ~10% of all
KIT mutations. Primary mutations in exons 13 (exceptionally
in exon 14) and in exon 17 are significantly rarer (Figure 2).
GIST with exon 11 and exon 9 primary mutations are signif-
icantly different in terms of biology, clinical behavior, and
response to treatments (Napolitano et al. 2022). From a molecular perspective, mutations in exon 11 activate KIT independently of SCF and the mutated protein is localized for the most
part intracellularly, whereas KIT with exon 9 mutations maintain partial ligand sensitivity and localization to the cell membrane (Shi et al. 2016).
Clinically, GIST with KIT exon 11 mutations can be found in
any anatomical site, whereas GIST with exon 9 mutations are
more frequently found in the intestine, where they represent up
to 25% of all diagnosed GIST. Moreover, in the advanced setting
KIT exon 11 mutant GIST usually respond well to treatment
with first-line imatinib, whereas exon 9 mutant have reduced
sensitivity. In these patients, progression-free survival (PFS)
can be improved with an increased dose of imatinib
(Gastrointestinal Stromal Tumor Meta-Analysis, 2010). Of
460 4 SPECIALIST ABDOMINAL CANCER MANAGEMENT TEAMS
Exon 13/14
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Exon 11
Exon 9
Exon 17
Figure 2 Frequency and molecular localization of the different primary
KIT mutations in GIST.
note, in a retrospective series of KIT exon 9 mutant patients
treated the adjuvant setting, a higher dose of imatinib was not
associated to a significant benefit over the standard dose
(Vincenzi et al. 2021). For second-line sunitinib, the PFS of
patients with KIT exon 9 mutations is longer than that of
patients with exon 11 mutations (Heinrich et al. 2008).
From a prognostic perspective, for KIT exon 11 mutant GIST,
the presence of the deletion of codons 557–558 has been associated to more aggressive clinicopathological features and
increased risk of relapse after surgery compared to the presence
of missense mutations (Martin et al. 2005). A negative prognostic impact of KIT exon 9 mutation has also been proposed,
but this is still debated as GIST in the small bowel are prognostically less favorable compared to those in other locations
regardless of the mutational status (Napolitano et al. 2022).
Mutations in exons 13/14 and in exon 17 are significantly
more common as secondary resistance mutations, and their
prognostic and predictive role when found as primary mutations is poorly defined (Lasota et al. 2008).
Germline mutations in KIT have been described in ~25 families. The syndrome is transmitted in an autosomal dominant
pattern, and these patients typically develop multiple or sometimes diffuse GIST, usually in middle age, and usually in the
stomach or small intestine. Other signs of KIT activation can
be present, including cutaneous hyperpigmentation, mastocytosis, and dysphagia. Prognosis varies, and many patients live
can long for a long time with the disease. Experience with imatinib treatment in familial GIST is very limited (Brodey et al.
2022; Meir et al. 2021).
PDGFRA
PDGFRα is a transmembrane receptor structurally and
functionally related to KIT. Primary mutations in PDGFRA are
mutually exclusive with KIT mutations, usually occur in gastric
GIST and more rarely in the small intestine. Some of these
tumors have weak or no detectable CD117 expression (Heinrich
et al. 2003).
A majority of PDGFRA mutant GIST have a favorable prog-
nosis reflecting the prognosis of gastric GIST. The most
common PDGFRA mutations (~80% of the total) are found in
exon 18, which encodes for the activation loop of the kinase
domain. The Asp842Val (D842V) substitution is most frequent. While most indels in exon 18 results in imatinibsensitive PDGFRA mutants, D842V-mutant GIST are resistant
to imatinib. In fact, the D842V substitution can be also acquired
during treatment with imatinib as a secondary resistance mutation. PDGFRA exon 12 (juxtamembrane domain) mutations
are relatively rare and are expected to be imatinib sensitive.
PDGFRA exon 14 mutations (ATP-binding domain) have been
reported in a few cases, and data on their sensitivity to imatinib
are inconclusive (Blay et al. 2021; Corless et al. 2005).
Less than 10 families with germline PDGFRA mutations have
been described so far. The so called PDGFRA-mutation syndrome is characterized by one or more of the following: multiple, stomach-restricted GIST without diffuse ICC hyperplasia;
inflammatory fibroid polyps; other unique phenotypic characteristics due to diffuse PDGFRα activation (Manley et al. 2018;
Ricci et al. 2015).
SDH
GIST with alterations in components of the SDH enzyme (collectively known as SDH-deficient GIST) are the most common
subtype of KIT/ PDGFRA wild-type GIST. They manifest predominantly in females and at a young age. They arise almost
exclusively in the stomach, are often multifocal and with epithelioid morphology, and tend to metastasize to the locoregional
lymph nodes and liver. Despite metastases, many patients survive a long time with the disease. From a diagnostic perspective,
SDH-deficient GIST are characterized by a negative immunohistochemistry for SDHB. Approximately 50% of the SDHdeficient GIST are caused by hypermethylation of the SDHC
promoter locus, 30% by SDHA mutations, and the remaining
20% by mutations in SDHB, SDHC, SDHD (Pitsava et al. 2021).
SDH-deficient GIST can be sporadic in nature, or associated
to two tumor syndromes, the Carney triad (CT, OMIM
#604287) and the Carney–Stratakis syndrome (CSS, OMIM
#606864). CT is a nonfamilial tumor syndrome characterized
by the combination of gastric GIST, pulmonary chondroma
(hamartoma), and paraganglioma. The median age of onset is
18 years, and there may be a long time span between the
appearances of the different components. There is a strong
female predominance (85%). Recent evidence support mosaic
constitutional epigenetic inactivation of the SDHC promoter
locus as the cause of CT. CSS is characterized by the presence of
23 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF GI STROMAL TUMORS 461
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GIST and paraganglioma, it affects both males and females
during childhood or adolescence. CSS is caused by germline
inactivating mutations in SDHB, SDHC, and SDHD and, more
rarely, SDHA (Boikos et al. 2016; Dwight et al. 2013; Gourinat
et al. 2015; Pasini et al. 2008; Pitsava et al. 2021).
NF1
NF1 patients have a significant predilection to GIST (risk
increased by 100–200-fold compared with non-NF1 patients),
and GIST are the most common GI mesenchymal tumors in
these patients, outnumbering nerve sheath tumors. The NF1associated GIST typically occur in duodenum, jejunum, and
ileum and only rarely in the stomach or colon. They occur in
slightly younger patients than sporadic GIST, are often multiple, including minimal GIST precursors, and are accompanied by diffuse Cajal cell hyperplasia. The course is indolent in
a majority of cases, although 10–15% of the patients have
mitotically active and clinically malignant GIST, more often so
in the duodenum. Morphologic features of NF1-associated
GIST are similar to those of sporadic intestinal GIST, and they
usually positively stain for CD117. In NF1-associated GIST, the
mutation in the NF1 gene is germline and somatic KIT and
PDGFRA mutations are absent (Andersson et al. 2005;
Miettinen et al. 2006).
Other KIT/PDGFRA Wild-type GIST
Other rare driver mutations reported in wild-type GIST include
activating mutations in BRAF or gene fusions involving NTRK3
or FGFR1. The identification of these alterations is becoming
increasingly important due to the development of effective targeted therapies (Agaram et al. 2008; Brenca et al. 2016;
Napolitano et al. 2021).
Management of Localized GIST
Surgery
Approximately 80% of patients presenting with GIST have primary localized disease without metastasis, when major sequelae
to resection are not expected. For them, complete surgical
resection is the standard of care and offers the only chance of
cure. Large, localized tumors or those challenging to resect
because of their location may require neoadjuvant therapy, if
the tumor harbors a mutation sensitive to available TKIs.
Importantly, while gastric micro- and mini-GIST can undergo
surveillance, non-gastric GIST should always be characterized
and treatment considered. Laparoscopic resection can be performed by experienced surgeons, and it is especially useful for
small gastric GIST (Casali et al. 2022).
Typically, a wedge or segmental resection of the organ from
which a GIST has arisen is sufficient. This is because GIST
grow exophytically from the gastrointestinal tract and do not
usually spread within the bowel wall. Unlike gastrointestinal
adenocarcinomas, GIST often just displace adjacent vital
structures and do not invade them. Nevertheless, when tumor
adherence to nearby structures does occur, partial resection
to achieve tumor clearance. The overall goal of surgery should
be to achieve gross tumor clearance with negative microscopic margins (R0), whenever possible. In patients with
low-risk GIST in unfavorable locations, a microscopically
positive margin (R1) can be accepted, as R1 resection has not
been formally associated with a worse overall survival. On the
contrary, intraoperative tumor rupture should be avoided as it
is associated to a considerably higher risk of relapse (Gronchi
et al. 2020).
Importantly, lymphadenectomy is not routinely performed, as
GIST do not usually metastasize to regional nodes. SDH-deficient
GIST, which are often multifocal and involve regional nodes, represent an exception. In these cases, resection should include pathologic lymph nodes if present, and it should be performed limiting
the extent of gastric resection (Weldon et al. 2017).
Patients with resected GIST are assessed for their risk of
recurrence and, in presence of imatinib-sensitive mutations,
they are offered adjuvant treatment with imatinib mesylate 400
mg daily for 36 months if their risk of relapse is considered high
(i.e. >50%). Ongoing studies are evaluating a longer duration of
the adjuvant treatment in patients at higher risk of recurrence.
In the case of KIT exon 9 mutations, the benefit of a higher dose
of imatinib in the adjuvant setting has not been convincingly
proven. Imatinib can also be offered in the neoadjuvant setting
to improve tumor resectability or allow for more conservative
surgical management. In these cases, surgery is usually performed after 12 months of treatment, or sooner at plateaux of
radiological response, and the combined duration of the neoadjuvant and adjuvant treatment is 36 months (Casali et al.
2022; Vincenzi et al. 2021).
Following surgery, the current guidelines advocate for patients
with intermediate/high-risk GIST a follow up with CT or MRI
scans of the abdomen and pelvis with intravenous contrast every
3–6 months during the first 5 years after resection depending on
the individual risk of relapse and yearly thereafter. For low-risk
tumors, the usefulness of a routine follow-up is not known, and
it could be carried out with scans every 6–12 months for 5 years.
Very low-risk GIST probably do not require routine follow-up,
although the risk is not zero (Casali et al. 2022).
Risk Assessment
The prognosis of GIST is highly variable, and a number of risk
assessment tools have been developed to stratify patients with
resected GIST based on their risk of developing local or distant
recurrence. These tools are based on the most well-characterized prognostic factors identified in GIST, namely tumor
462 4 SPECIALIST ABDOMINAL CANCER MANAGEMENT TEAMS
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Tumor parameters Risk of recurrence
Risk assessment table. Adapted
Table 1
from Miettinen and Lasota (2006).
Size Mitotic rate (per 50
≤2 cm ≤5 0%
>2 cm ≤5 cm 1.9%
>5 cm ≤10cm 3.6%
>10 cm 12%
≤2 cm >5 0% * 50% * N/A 54%
>2 cm ≤5 cm 16%
>5 cm ≤10cm 55%
>10 cm 86%
* denotes tumor categories with very few cases
** combined groups because of small number of cases
high power fields)
location, dimension, mitotic count. The most widely used
classification, developed by Miettinen and Lasota, categorizes
the risk of recurrence in four groups (very low, low, medium,
high). As a rule, gastric location, a largest dimension < 5 cm
and a mitotic count < 5 mitosis/50 high power fields (HPFs) or
5 mitosis/5 mm
2
are associated to a lower risk of recurrence
(Table 1).
More recently, contour maps have been developed, which
Gastric GIST Jejunal and
none
very low
low
moderate
moderate
high
high
Ileal GIST
0%
none
4.3%
low
24%
moderate
52%
high
73%
high
85%
high
90%
high
Duodenal GIST Rectal GIST
0%
none
8.3%
low
34%
high **
50%
high
86%
high **
0%
none
8.5%
low
57%
high **
high
52%
high
71%
high **
gene expression profiles of gastric versus small intestinal GIST
have been noted (Hemming et al. 2021).
The expected prognosis in different categories is clinically
relevant, as it is used to select patients at high risk of relapse
possibly requiring adjuvant treatment and may offer guidance
for surveillance strategies.
The treatment of localized imatinib-sensitive GIST can be
summarized in the following algorithm (Figure 3).
evaluate tumor dimension and mitotic count as a continuous
rather than categorical variable, and also include intraoperative
tumor rupture in their models (Joensuu et al. 2012; Miettinen
and Lasota 2006).
Management of Advanced GIST
Systemic treatment of advanced GIST with conventional sarcoma chemotherapy has generally been ineffective. Targeted
Knowledge Gap
therapies with tyrosine kinase inhibitors (TKIs) represent
the standard of care in metastatic and unresectable GIST. In
• Additional but less documented prognostic markers are Ki67
(MIB1) labelling index and expression of p53. Furthermore,
the specific contribution to the risk of recurrence of specific
driver mutations, such as KIT exon 9 or KIT exon 11 deletion of
many cases, tumors will develop resistance associated to the
development of secondary mutations in the same RTK genes.
Other mechanisms of resistance depend however on adaptive
upregulation of other oncogenic pathways.
the codons 557–558, is highly debated.
While the prognostic impact of tumor dimension and mitotic
count is easy to reconcile, it is more difficult to explain the reasons why intestinal GIST behave more aggressively than gastric
GIST with similar tumor size and mitotic rate. The biologic
background of this is largely unknown, although differences in
Surgery and Local Therapies in Advanced GIST
Local therapies are increasingly finding space in the
management of advanced GIST patients. When discussed
within expert multidisciplinary tumor boards, they can be
offered in different settings and with different goals.
23 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF GI STROMAL TUMORS 463
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Figure 3 Treatment algorithm of localized GIST patients with imatinib-sensitive mutations.
Patients with low burden of disease responding to imatinib
or other TKIs (in particular, those with metastatic disease
limited to the liver) could be considered for surgery or other
local treatments to residual disease.
Other cases wherein surgery and local therapies are considered are the treatment of:
• symptomatic lesions, as in the case of radiotherapy for bone
metastases,
• oligo-progressive metastases, to treat a TKI-resistant clone of
disease and defer the change of systemic treatment,
• metastasis with intralesional hemorrhage, fistulation, or
causing bowel obstruction.
have a small tumor burden at imatinib initiation survive
longer than those who have a large burden, which lends
support to early initiation of imatinib therapy for GIST
patients who are diagnosed with sensitive disease. KIT/
PDGFRA wild-type GIST are known to be poorly sensitive to
imatinib and ongoing studies are exploring whether other
large spectrum TKIs such as regorafenib might have a higher
efficacy in this population. Overall, only 10–15% of all
patients have a GIST that is primarily resistant to imatinib
(Casali et al. 2022).
Imatinib-sensitive GIST are usually treated with a dose of
400 mg once daily. Food has no relevant impact on the rate or
extent of imatinib bioavailability, and because imatinib may
cause local irritation, it is taken with food. The drug is pri-
First-line Treatment
The first-line treatment of GIST patients depends on the
mutational status of the disease. GIST with imatinib-sensitive primary mutations (almost all the most common primary KIT and PDGFRA mutations, except for the PDGFRA
D842V mutation) are treated with imatinib. Patients who
marily metabolized in the liver by the cytochrome P450 (CYP)
3A4 or CYP3A5 and has a fecal to urinary excretion ratio is
approximately 5:1 (Peng et al. 2005).
Of all GIST patients carrying imatinib-sensitive mutations,
approximately 60–80% will achieve a partial response (PR)
during treatment, and another 20–30% will have stable disease
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(SD) as best response. The presence of a KIT exon 11 is associated to a higher likelihood of response to imatinib, whereas
GIST with exon 9 can display primary resistance and are less
likely to respond. Importantly, patients with SD as best response
achieve similar overall survival to patients with a radiological
PR. The median response duration of advanced GIST to imatinib treatment is ~24 months, although some patients have
shown responses lasting over 5 years, without development of
any significant resistance. The presence of KIT exon 11 mutation is also associated with a longer median time to imatinib
failure as compared to exon 9 mutation (Blanke et al. 2008a).
The use of a higher dose of imatinib (e.g., 800 mg daily) has not
been associated to better outcomes in KIT exon 11 mutated
GIST patients, and it is therefore not recommended as an initial
treatment in this population. On the other hand, the use of a
higher dose of imatinib was associated to a longer PFS in
patients with KIT exon 9 mutation. Based on these results, imatinib at a dose of 800 mg daily can be offered, whenever national
or local policies allow it, as a front-line treatment for patients
with KIT exon 9 GIST or upon progression to the standard
dose of imatinib in presence in patients with GIST carrying
other imatinib-sensitive mutations (Casali et al. 2022;
Gastrointestinal Stromal Tumor Meta-Analysis Group 2010).
Tumor response to imatinib is usually monitored with CT or
sometimes with MRI. The median time to radiological response
is 3–4 months when response to imatinib is assessed using conventional response criteria that are based on tumor volume
reduction. Patients may obtain subjective benefit within only a
few days after starting treatment, which for this reason should
be started at the earliest time possible in symptomatic patients,
even in those with a poor performance status. No study has
evaluated the optimal frequency of response evaluation examinations, which is currently unknown. In clinical practice the
first follow-up CT is often carried out 2–3 months after
initiation of imatinib, and the subsequent evaluations at
approximately 3-month intervals. Metabolic imaging with
FDG-PET may occasionally help in the clinical decisionmaking, as a diminished uptake of FDG in a PET scan may be
found within a few hours or days after initiation of imatinib
treatment in sensitive patients (Stroobants et al. 2003).
Responding liver metastases characteristically become
hypodense on CT or MR imaging following initiation of imatinib
treatment. This is due to cell-rich tumor tissue being replaced by
hyaline degeneration. Hypodense GIST metastases are better
delineated and more easily detected in a CT scan than the denser
untreated GIST lesions, which may result in visualization of a
greater number of small liver lesions in a CT scan or MRI upon
treatment (Figure 4). This must not be misinterpreted as tumor
progression. FDG-PET may be helpful in making a differential
diagnosis between tumor progression and response in problematic cases. Decrease in metastatic lesion density usually heralds
response and lesion volume reduction (Choi et al. 2007).
Imatinib is recommended to be administered continuously
without planned breaks in its administration. In case of disease progression following interruption, most patients respond to imatinib
reintroduction. Interruption of imatinib administration is unlikely
to be beneficial, and continuous imatinib with no upper limit for
administration duration is the current standard in the treatment of
advanced GIST. Since imatinib dose reductions are best avoided,
it is important to know how to manage common adverse effects.
Many adverse effects are mild to moderate in severity and may not
require any specific therapy. The most
frequent adverse effects of
imatinib are periorbital or leg edema, occasional muscle cramps
in fingers and feet, diarrhea, nausea/vomiting, fatigue, and skin
rash. Grade 1 or 2 macrocytic anemia, neutropenia and elevation of serum transaminase levels are also common. Periorbital
edema may respond to diuretics and muscle cramps to calcium
or magnesium supplementation. Imatinib-related nausea may be
Figure 4 GIST metastases in the
liver. (a) Before initiation of imatinib.
(b) The metastases have decreased in
size and become hypointense
following initiation of imatinib
administration.
23 EPIDEMIOLOGY, PATHOLOGY, DIAGNOSIS, PREVENTION, AND MANAGEMENT OF GI STROMAL TUMORS 465
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alleviated when the daily imatinib dose is divided and administered twice daily. Imatinib therapy requires close surveillance,
especially at the beginning of the treatment and when the patient
is elderly or frail, and when multiple concomitant medications
cannot be avoided. Generalized skin rash or edema, grade 3 or
4 cytopenias, and dyspnea (may herald interstitial lung disease)
require prompt interruption of imatinib administration, and often
lead to subsequent dose reduction.
PDGFRA D842V-mutated GIST have been recently shown to
respond exceptionally well to the next-generation TKI avapritinib, even at the relatively low doses trialed within a phase I
study. In the NAVIGATOR phase I trial, the overall response
rate (complete responses, CR, + PR) was 91% and the clinical
benefit rate (CR + PR + SD) was 98% with durable responses.
The toxicity profile of avapritinib was characterized by gastrointestinal symptoms (nausea and vomiting) and variable neurocognitive toxicity, which might require frequent dose
interruptions or reductions (Jones et al. 2021).
KIT/PDGFRA wild-type GIST patients represent a difficult-totreat population: in SDH-deficient GIST, there may be some benefit
from available TKIs, with reports of activity of sunitinib and regorafenib. Patients with GIST carrying NTRK rearrangement should
be treated with an NTRK inhibitor and those with BRAF mutations
may benefit from BRAF inhibitors (Casali et al. 2022).
patients with KIT exon 9 mutation, sunitinib was significantly
superior to ripretinib (Bauer et al. 2022).
Third-line Treatment
Regorafenib at a starting daily dose of 160 mg in a 3 weeks on and
1 week off schedule has activity in GIST patients in third-line, as
demonstrated in the GRID trial (Demetri et al. 2013). In this study,
the median progression-free survival with regorafenib was 4.8
months, compared to less than one month for placebo. The toxicity profile of regorafenib is similar to the one of sunitinib, with
hypertension, palmar-plantar erythrodysesthesia and diarrhea
reported in 40–50% of all patients. As for the case of sunitinib, personalized schedules of regorafenib might be better tolerated and
associated to good clinical outcomes (Nannini et al. 2021).
Importantly, similar benefits from regorafenib are observed
in patients whose tumors harbored primary KIT exon 11 or
exon 9 mutations, and across various secondary KIT mutations
(Jeffers et al. 2022).
The randomized Phase 3 VOYAGER trial showed no
significant difference in progression-free survival between
regorafenib and avapritinib as third-line or later treatment in
patients with molecularly unselected, unresectable or metastatic GIST (Kang et al. 2021). Therefore, regorafenib remains
the standard of care in this setting.
Second-line Treatment
In the event of disease progression on first-line imatinib at 400
mg once daily, dose escalation to 800 mg daily has been proposed as a potential treatment for patients with manageable
side effects at the lower dose. About one third of these GIST
patients will show radiological stability or response with the
higher dose (Blanke et al. 2008b; Verweij et al. 2004). Regulatory
constraints may now limit this practice, also considering the
availability of further lines of treatment.
The accepted standard of care in second-line is the TKI sunitinib
given orally once daily at a 50 mg starting dose in 6-week cycles
with 4 weeks on and 2 weeks off treatment, with a median time to
tumor progression of approximately 7 months (Demetri et al.
2006). Treatment with sunitinib can be associated to significant
side effects, with hypertension and palmar-plantar erythrodysesthesia reported by approximately 50% of all treated patients. A continuous dosing of sunitinib at 37.5 mg can be alternatively
considered and might be better tolerated (George et al. 2009).
The activity of sunitinib is significantly influenced by both
primary and secondary KIT mutations. In particular, the
activity of sunitinib was more pronounced in patients carrying
primary KIT exon 9 mutations (median time to progression of
approximately 12 months), as well as in those with secondary
KIT exon 13 or 14 mutations, rather than exon 17 or 18 mutations (Heinrich et al. 2008; Reichardt et al. 2016).
More recently, in the INTRIGUE trial, the next-generation
TKI ripretinib failed to show superiority compared to sunitinib
in this setting, despite meaningful clinical activity and improved
tolerability compared to sunitinib. Importantly, in the subset of
Fourth-line Treatment
In the pivotal INVICTUS trial, ripretinib at a dose of 150 mg
once daily showed meaningful clinical activity in GIST patients
in the fourth line of treatment, with a median progression-free
2020). In patients benefitting from ripretinib, intra-patient
dose escalation to 150 mg twice daily can be associated to
further clinical benefit (George et al. 2021; Zalcberg et al. 2021).
Notably, in this setting ripretinib showed activity across
broad mutation subgroups (Bauer et al. 2021), consistent with
its novel mechanism of action as a switch-control TKI, specifically developed to target both primary and secondary KIT and
PDGFRα resistance mutations (Goggin et al. 2022).
The treatment of advanced GIST can be summarized in the
following algorithm (Figure 5).
Conclusion
Over the last decades, the integration of multiple treatment
modalities is becoming increasingly important in the
management of GIST patients. Surgery, once limited to the
localized setting, is now also part of the integrated management
of advanced GIST patients, together with other local therapies.
Historically, GIST has represented the first example of a solid
tumor wherein targeted therapies with TKIs has led to dramatic
changes in the natural history of the disease, and it continues even
today to represent a model to study the impact of secondary mutations in kinases and to develop new and more effective inhibitors.
The key principles of management of GIST are summarized
in Table 2.
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Figure 5 Treatment algorithm of advanced/metastatic GIST patients.
Table 2 Key principles in the management of GIST.
Clinical scenario Management
Local disease Complete surgical removal of the tumor with free (usually > 1 cm) margins.
Avoid tumor rupture.
Consider neoadjuvant treatment with imatinib in presence of GIST with imatinib-sensitive mutations, if R0 surgery with no
major sequelae is difficult to achieve.
Adjuvant imatinib recommended in case of high-risk tumors with imatinib-sensitive mutations.
Recurrent/metastatic
disease; first-line therapy
GIST progresses during
imatinib therapy
Imatinib-sensitive mutations: imatinib daily until treatment failure; starting dose is usually 400 mg (900 mg/day can be
considered for GIST carrying KIT exon 9 mutations). Monitor blood cell counts, blood chemistry and treatment response.
Surgical resection of residual tumours of responding patients may be considered in selected cases, but the benefit is
unproven. Removal of bleeding, infected or obstructing metastases may be necessary.
Avapritinib for patients with PDGFRA D842V GIST, if available.
Other targeted therapies or clinical trials with novel agents in presence of GIST with imatinib-insensitive mutations.
Check for compliance of taking imatinib – if available, monitor blood levels of imatinib.
Consider surgery or local treatments for single growing metastases. Such metastases may harbor a new gene mutation
that renders GIST resistant to imatinib.
Escalate imatinib dose up to 800 mg/day, if feasible.
Second-line: sunitinib.
Third-line: regorafenib.
Fourth-line: ripretinib.
Participation in a clinical trial with novel agents.
Palliative surgery or radiation therapy in selected cases.
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