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Gastrointestinal Stromal
Tumours
Dr. Uttam Laudari
JR III
Department of Surgery
Kathmandu Medical College

Introduction
• GIST are rare malignancies
• most common sarcoma of the GI tract
• represent only 0.2% of all GI tumors,
• subject of considerable clinical and experimental interest, because of the
identification of their activating signal (oncogenic mutation
of the c-kit receptor) and
the development of a therapeutic agent that suppresses
tumor growth by inhibiting this signal

• Diagnosis of GIST has dramatically increased since 1992, and
survival has greatly improved since 2002, when imatinib
mesylate was approved by FDA for GIST
Perez EA, Livingstone AS, Franceschi D, et al. J Am Coll Surg 2006;202:623–629

Epidemiology
• Most common mesenchymal tumour of the GI tract
• arises from a common precursor cell, which gives rise to the
interstitial cells of Cajal
• Most of these gastrointestinal (GI) sarcomas are GISTs
• The age-adjusted yearly incidence rate of GIST was 6.8 per
million in the SEER data from 1992 to 2000;
• 54% were men and 46% were women

• In a series of consecutive autopsies performed in
Germany, small GISTs (1 to 10 mm in size) were
grossly detectable in 22.5% of the autopsies in
individuals older than 50 years
Agaimy A, Wunsch PH, Hofstaedter F, et al. Minute gastric sclerosing
stromal tumors (GIST tumorlets) are common in adults and
frequently show c-KIT mutations. Am J Surg Pathol 2007;31: 113–120

• Similarly, in a series of 100 whole stomachs resected from
Japanese patients diagnosed with gastric cancer, microscopic
GISTs were found in 35 of the 100 stomachs
Kawanowa K, Sakuma Y, Sakurai S, et al. High incidence of microscopic
gastrointestinal stromal tumors in the stomach. Hum Pathol 2006;37:1527–
1535

• Median age of adults at diagnosis of GIST ranges from 66 to 69 years
• In a study of 1765 GISTs arising from the stomach, the median age at diagnosis was
63 years
– Miettinen M, Sobin LH, Lasota J. Am J Surg Pathol 2005;29:52–68
• In a series consisting of 906 jejunal and ileal GISTs, the mean age was 59 years
– Miettinen M, Makhlouf H, Sobin LH, et al. Am J Surg Pathol 2006;30: 477–
489

Presentation
• GISTs can occur anywhere along the GI tract
• Most common in the
–stomach (50%)
– small bowel (25%)
– Colon (10%),
– omentum/mesentery (7%)
– esophagus (5%) are less common primary sites
• A few GISTs occur within the abdomen and retroperitoneum

• Liver metastases and/or dissemination within the abdominal
cavity are the usual clinical manifestations of malignancy
• Lymph node metastases are extremely uncommon

Pathology
• Arise from the interstitial cells of Cajal (ICC),
– components of the intestinal autonomic nervous system
– pacemakers regulating intestinal peristalsis

• GISTs range in size from incidental lesions a few millimeters in
diameter to large masses of 35 cm or more
• the median size at presentation is about 5 cm

• Tumors are generally centered on the bowel wall but may
form polypoid serosal- or mucosal-based masses
• Ulceration of the mucosa is often associated with GI
bleeding

• Most GISTs present as a single, well-circumscribed nodule.
• The cut surface is fleshy and may show areas of cystic
degeneration, necrosis, or hemorrhage
• Occasionally, satellite nodules are within the adjacent muscularis
propria
or serosa
• Rarely 2 separate GISTs at different locations in the GI tract are
present
familial GIST

• Most GISTs show 1 of 3 histologic patterns:
– predominantly spindle cells (the most common pattern)
– predominantly epithelioid cells
– a mixture of both spindle and epithelioid cells

• Epithelioid GISTs
– diffuse or nested architecture,
• spindle cell GISTs
– short fascicles or whorls
• Stroma is usually scanty
Spindle cell type
Epitheloid cell type

Immunohistochemistry
• characteristic immunohistochemical profile
– 95% are positive for KIT (CD117)
– 60% to 70% for CD34
– 30% to 40% for smooth muscle actin
– 5% for S-100 protein
– 1% to 2% for desmin
– and 1% to 2% for keratin

 Leiomyoma and leiomyosarcoma - desmin and negative for
KIT
 Malignant melanoma --immunoreactivity for S-100 protein
 Schwannomas --immunoreactive for S-100 protein and
negative for KIT
 Malignant peripheral nerve sheath tumors and
desmoid
fibromatosis are negative for KIT

Prognosis
• 2 most important prognostic features of a primary tumor are
its size and mitotic index
• Small lesions may remain stable for years

• features associated with a poor prognosis include
– large size (>5 cm)
– increased mitotic activity
• In some studies, location of the tumor in the small
bowel indicated a worse outcome

• All GIST have malignant potential
1. Miettinen M, Sobin LH, Lasota J. Am J Surg Pathol 2005;29:52–68.
2. Miettinen M, Makhlouf H, Sobin LH, et al.. Am J Surg Pathol 2006;30: 477–489.
3. Miettinen M, Lasota J. Gastrointestinal stromal tumors—Virchows Arch 2001;438:1–12.

Significance of Kinase Mutation
Status
• 80% -oncogenic mutation in the KIT tyrosine kinase
• 5%–7% -mutation in the KIT-homologous tyrosine kinase PDGFRA
• 10% to 15% of GISTs are negative for KIT and PDGFRA gene mutations
• wild-type GISTs

• KIT mutant- sensitive to Imatinib
• PDGFRA confers complete resistant to imatinib

Clinical features
• Are usually asymptomatic and discovered upon imaging or at
laparotomy for other reasons
• With advanced disease presentation may be a mass lesion or
vague abdominal pain
• bleeding ( Can cause life-threatening hemorrhage )
• Obstruction / perforation

• Between 15–50% of GIST present with overtly metastatic disease
– common metastatic sites being liver and peritoneum
with less than 5% of patients demonstrating pulmonary metastases

• Almost never metastasize to regional lymph nodes
• Can invade adjacent organs, the common sites being intestine, liver, or
bladder
• fistulas with bowel, the biliary tree, or the skin, enterocutaneous fistula

Diagnosis
Imaging
• UGI Endoscopy
• Submucosal lesion, with or
without ulceration, present in the
upper or lower GI tract
• Are visually indistinguishable from
other GI tumors of smooth
muscle origin

Endoscopic Ultrasound
• Commonly present as
submucosal tumors
in the wall of the GI tract
• Central necrosis of high-risk
tumors or erosion into blood
vessels can produce local
inflammation or significant GI
bleeding

CT Scan
• Seen as solid hyperdense-enhancing
mass
• Critical to determine the anatomic
extent of a GIST and to assist with
operative planning
• Ghanem and colleagues
recently reported
 Small GIST
Sharp margins
Intraluminal growth
pattern
Homogenous density on
both
unenhanced and contrast-enhanced
scans

CT Scan
 Larger GIST
Irregular margins
Extraluminal
growth patterns
Inhomogeneous
density
• Radiographic signs for aggressive
malignant GIST include
calcification, ulceration, necrosis,
cystic areas, fistula formation,
metastasis, ascites, and signs of
infiltration of local tissues

PET Scan
• Useful in addition to CT for
evaluating GIST, particularly
as a means of assessing
response to chemotherapy
• Metabolically active GIST
accumulate 18FDG, and
blockade of the KIT receptor
results in a rapid suppression
of this activity

Management
Medical Treatment
• Median survival for patients with GIST who are treated with standard
cytotoxic chemotherapy is generally less than 2 years (range 14–18
months)

Imatinib mesylate
• Selective, potent, small molecule inhibitor of tyrosine kinase
signaling enzymes
KIT, ABL family of tyrosine kinases, including the
leukemia specific BCR-ABL chimera, PDGFR
 Both mutant and non-mutant forms of KIT can be inhibited by
exposure to imatinib

What optimal dose of imatinib should be used
to begin dosing for patients with advanced
metastatic or unresectable GIST?
• Two separate phase III trials have been conducted
North American Sarcoma Intergroup, consisting of U.S. cooperative oncology
groups (SWOG, CALGB [Cancer and Leukemia Group B], ECOG [Eastern
Cooperative Oncology Group]) and the National Cancer Institute of Canada
(NCIC) Sarcoma Group
EORTC Sarcoma Group aligned with AGITG and the Italian Sarcoma Group
(ISG)

• Each one of these large phase III trials in patients with advanced
GIST compared imatinib given orally at 2 different doses: 400 or
800 mg daily (given as split doses of 400 mg twice a day) in
patients with metastatic or unresectable GIST
• Both studies showed
Higher dose of imatinib was associated with more side
effects than the lower dose
Euivalent response rates and overall
survival for both
dose levels

Patients with unresectable disease that is progressing on higher-
dose imatinib (resection should only be considered in patients
with localized progression) are candidates for therapy with
sunitinib

Sunitinib Malate
• Oral TKI that is less specific than imatinib mesylate
• In addition to inhibiting KIT and PDGFR, sunitinib acts on vascular
endothelial growth factor receptors (VEGFR1- 3), Tyrosine kinase-3,
colony-stimulating factor 1
• Possesses potential antiangiogenic activity in addition to antitumor
action related to receptor tyrosine kinase inhibition
• Preclinically, sunitinib inhibits some KIT mutant isoforms that are
resistant to imatinib

Surgery
• Mainstay of therapy for patients with primary GIST who do not have evidence of
metastasis
• Should be the initial therapy if the tumour is technically resectable with acceptable
risk of morbidity
• For both large tumors and poorly positioned small GISTs that are considered
marginally resectable on technical grounds, neoadjuvant imatinib is
recommended
• Patients with primary localized GIST whose tumors are deemed
unresectable
should also start imatinib

Goal of Surgery
Complete gross resection with an intact pseudocapsule and
negative microscopic margins

Post Surgical Follow Up
• Typical sites of tumor recurrence following resection of a GIST with
curative intent are the local resection bed, the liver,
and the peritoneum
• Pulmonary metastases are uncommon
• Time to recurrence reflects the original growth pattern of the tumor, and
recurrences as early as 3 months following resection have been observed

Post Surgical Follow Up
• Because more recurrences occur within the first 5 years after
surgery
– imaging intervals of 3 to 6 months are standard for patients in
the first 5 years of post treatment follow-up, with annual evaluation
thereafter

• Localized GIST  Surgery Recurrence In 5 year
– Low risk- 2-5%
– High Risk- 70-90%
• In absence of adjuvant therapy
– approximately 50% of patients receiving potentially curative
surgery will develop either locally recurrent or metastatic disease within
5 years
– yielding 5-year survival rates of 40–55%
• Effectiveness of imatinib in managing metastatic disease has
led to combined modality treatment of high-risk localized
tumors
Adjuvant Therapy

Metastatic GIST
• At present, all unresectable, recurrent, and metastatic GIST
are considered for therapy with imatinib
• Median time to an objective response is approximately three
months

Metastatic GIST
• Indications for surgery are
1) disease that is stable or shrinking on TKI therapy when complete gross
resection is possible (stable disease)
2)isolated clones progressing on TKI therapy after initial response
(indicative of secondary drug resistance), while other sites of disease remain
stable (limited disease progression)
3) emergencies including hemorrhage, perforation, obstruction, or abscess

Disease Response and Progression
• PET scanning can be used to rapidly assess changes in tumor
metabolism that reflect effective disease suppression by imatinib
• Changes seen on CT scan may take months to become apparent
Shrinkage in size
When palpable, become noticeably softer
Cystic transformation of lesions, a change that is most easily
detected in the liver
Quiescent disease appears as completely homogeneous, fluid-filled
structure

Disease Response and Progression
• Decreased density on contrast-enhanced CT of responding
GISTs indicates response to therapy and correlates with tumor
necrosis or with cystic or myxoid degeneration

Choi HC, Macapinlac HA, Burgess MA, et al. Proc Am Soc Clin Oncol 2003;22:819. Abstract 3290
Choi H, Charnsangavej C, Faria SC, et al. J Clin Oncol 2007;25:1753-1759.
Choi H, Charnsangavej C, Faria SC, et al.. Am J Roentgenol 2004;183:1619–1628.

PET Scan
• Good response to imatinib is observed on FDG-PET as a marked decrease
in 18FDG uptake in the tumors
• Response can be seen as early as 24 hours after a single dose of imatinib
• Median time to CT response measured by tumor shrinkage is about 3–
4 months, whereas FDG-PET imaging can detect response within
hours to days

• Re-emergence of glycolytic activity as shown by FDG-PET in the follow-up of
patients on imatinib is consistent with secondary resistance to the drug or with
lack of compliance to the drug regimen
“Flare” phenomenon
• Suggested that portions of the tumor were still responding to imatinib, while other
parts had developed a new clonal evolution resistant

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