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Approach to Gastrointestinal Stromal Tumors (GIST)
David A. Kooby, M.D.Associate Professor of Surgery
GIST
Gastrointestinal Stromal Tumors (GISTs)
• Described in 1983
• Type of sarcoma• Cancer of mesenchymal origin• Smooth muscle and neural elements• Intestinal pacemaker cells (interstitial cells of Cajal)
• Epidemiology• ~1000-1500 cases annually in the United States• 6% of sarcomas• 80% of GI sarcomas
• Median age at presentation is 60Miettinen M et al. Hum Pathol. 1999;30:1213-1220.Joensuu H et al. Lancet Oncol J. 2002;3:655-664. Kindblom LG. Ann Oncol. 2002;13:157. Abstract 5770.Sircar K et al. Am J Surg Pathol. 1999;23:377-389.Wang L et al. Arch Pathol Lab Med. 2000;124:1471-1475.
GIST
Historical Misclassification
7%
13%
18%
34%
28%
GIST (~40% high risk)
Leiomyoma (benign)
Leiomyosarcoma (malignant)
Leiomyoblastoma (malignant)
Other
Variable criteria / confusing nomenclature
Higher incidence than thought
80% of GI soft tissue tumors now identified
Kindblom LG et al. Ann Oncol. 2002;13:157. Abstract 5770. Kindblom LG. www.peerviewpress.com/asco2003c.
Smooth muscle tumors all sites
Genetic Basis for GIST
• Genetic mutation
• c-kit proto-oncogene
• Exon 11: Gain of function mutation
• KIT protein over-expressed
• Kit protein function
• Transmembrane receptor
• Activated by stem cell factor ligand
• Increases tyrosine kinase activity
• Cascade of intracellular signals
Hirota S, et. al. Science. 1998;279:577-580.
SCF
TK
TKA
EXON 11
Extracellular
Intracellular
GIST
Normal KIT Function
Normal function of KIT protein:
– Hematopoiesis
– Melanogenesis
– Fertility and gametogenesis
Kit activation effects:
– Proliferation
– Differentiation
– Apoptosis / survival
– Adhesion / chemotaxis
– Angiogenesis
Taylor ML, Metcalfe DD. Hematol Oncol Clin North Am. 2000;14:517-535.
GIST
c-kit Gene Mutations
TK1
TK2
Extracellular
Intracellular
EXON 9 (~5%–10% of mutations)
EXON 11 (~70% of mutations)
EXON 13 (~5% of mutations)
EXON 17 (~5% of mutations)
Kinase insert
Ligand (SCF)-binding
.Heinrich MC et al. Hum Pathol. 2002;33:484-495.Corless CL et al. Proc Am Assoc Can Res. 2003;44. Abstract R4447.
7% of GISTs have a PDGFR mutation
GIST
KIT Mutations Predict Overall Survival
0 100 200 300 400 500 600 700 8000
10
20
30
40
50
60
70
80
90
100
Days
Ov
era
ll s
urv
ival
(%
)
KIT exon 11 (n=85)
KIT exon 9 (n=23)
No kinase mutation (n=9)
Heinrich et al. J Clin Oncol. 2003;21:4342.
GIST
Classification
• Immunohistochemistry
• CD117 (c-kit) positive (95%)
• CD34 positive (70%)
• Smooth muscle actin positive (40%)
• PS100 positive (5%)
• Desmin positive (2%)
• Molecular analysis
• CD117 negative cases (5%)
• KIT mutation
• PDGFR mutationCD117 (c-kit) positive
Miettinen M, Lasota J. Virchows Arch. 2001;438:1-12.
GIST Clinical Presentation
• Asymptomatic
• Incidental finding (11%)
• Symptomatic
• Vague GI pain or discomfort (38%)
• Abdominal mass (20%)
• GI hemorrhage
• Anorexia, weight loss, nausea, anemia, shortness of breath
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.
GIST
Ulcerated Gastric GIST
GIST
Anatomic Location
GISTs may occur anywhere in the GI tract/abdomen
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.
Site Incidence
Gastric 50%–70%
Small Intestine 20%–30%
Colon <5%
Other <5%
Other- omentum, mesentery, retroperitoneum, esophagus
GIST
Left Upper Quadrant Mass
Liver
Spleen
GIST
Initial workup
• Diagnosis• EGD
• Characterize a mass• Histology is can be difficult to obtain
• Staging (CT or MRI)• Evaluate the extent of the mass
• Detect metastases
• Assess tumor resectability
• 18FDG-PET
• Endoscopic ultrasound
Demetri et al. JNCCN. 2007;5(suppl 2):S1-S29.
GIST
CT Imaging of Primary Disease
GIST
Staging
High Risk (~40%)
• Primary with unfavorable features
• Metastasis
• Invasion of adjacent organs, structures
• Recurrence
Low Risk (~60%)
• Primary with favorable features
• Can still spread
Miettinen M et al. Hum Pathol. 1999;30:1213-1220.DeMatteo RP et al. Hum Pathol. 2002;33:466-477.
GIST
Staging
• Tumors classified as low risk can metastasize
Fletcher CD et al. Hum Pathol. 2002;33:459-465.Tornoczky T et al. J Clin Pathol. 2003;56:363-367.
Prevalence Risk Size Mitotic Rate
Very Low
Low
Intermediate
High
Overtly Malignant
<2 cm
2–5 cm
<5 cm
5–10 cm
>5 cm
>10 cm
Any size
<5/50 hpf
<5/50 hpf
6–10/50 hpf
<5/50 hpf
>5/50 hpf
Any mitotic rate
>10/50 hpf
98/106
31/106
GIST
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
Es
tim
ate
d p
rop
ort
ion
of
su
rviv
ors
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Time since diagnosis (years)
Very low 12
Low 33 65
Intermediate 20
Normal population
High 23
Overtly 12 35 malignant
Overall Survival by Risk Group
Risk groups % of Patients
GIST
Proposed Mechanism of gleevec
TK
TKA
EXON 11
Extracellular
Intracellular
STI571• A selective tyrosine kinase inhibitor of:
– Bcr-Abl
– PDGF-R
– Kit
• First used in Philadelphia chromosome–positive (Ph+) CML
– Target Bcr-Abl
Druker BJ et al. Nat Med. 1996;2:561-566.
GIST
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
Marked Biologic Response Revealedby PET Scan
Multiple liver and upper abdominal 18FDG-accumulating metastases
A marked decrease in 18FDG uptake4 weeks after starting imatinib mesylate
GIST
Ramifications of gleevec
• Treatment of metastatic and unresectable disease
• Adjuvant therapy?• Which patients?
• How long?
• Does it reduce recurrence?
• Does it improve survival?
• Are bridges burned?
• Neoadjuvant therapy?• Which patients?
• How long?
GIST ACOSOG Trial Z9001:phase III randomized, multicenter trial
adjuvant gleevec vs. placebo
Resected GIST 3 cm
Confirm Kit+GIST
400mg/day
Placebo
Recurrence800 mg/day
No recurrence,continue 1 year
Recurrence, switch to gleevec
No recurrence,continue 1 year
RecurrenceRestart gleevec
1 year Follow-up>5 yearsObjectives:
1) Overall survival2) Recurrence-free survival3) Safety of gleevec in the adjuvant setting
GIST
Z9001, Recurrence-free survival
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
Years, post-resectionPer
cent
al
ive
with
out
recu
rren
ce
GIST
Years, post-resection
Per
cent
al
ive
Z9001, Overall survival
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
GIST
Z9001, Conclusions
•Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with palcebo after the resection of primary gastroinstestinal stromal tumour.
DeMatteo R, et al. The Lancet. 2009;373: 1097-1104
GIST
Surgery for Primary GIST
• Fragility of tumor risks rupture
• Bleeding (tumor vessels)
• Dissemination
• Abdomen should be examined for metastases
• Peritoneal surfaces
• Liver
• Lymph node dissection unnecessary
• <5% incidence of nodal involvement
• GIST can often be lifted off surrounding organs
• “Pushers not Invaders”Demetri et al. JNCCN. 2004;21(suppl 1):S1.
GIST
Pushing tumors
GIST Laparoscopic resection of gastric GISTLong-term outcomes
• 50 patients in 8 year interval
• Tumor characteristics
• Mean tumor size 4.4 cm
• 9 (18%) had >10 mitotic figures/50 HPF
• Majority in proximal stomach
• Operative characteristics
• Mean operative time 135 min
• Mean blood loss 85 cc
• Follow up (mean 36 months)
• No port site recurrences
• 46 (92%) disease free
Novitsy YW, et al. Ann Surg. 2006 June; 243: 738–747.
Conclusion:Laparoscopic approach to small – medium sized gastricGISTs may be preferred over the open approach
GIST
Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.
Suggested port placement
GIST
Laparoscopic resection of gastric GIST
Novitsy YW, et al. Ann Surg. 2006 June; 243(6): 738–747.
GIST Laparoscopic Versus Open Gastric Resections for GIST: A Size-Matched Comparison.
Lap (N=40) Open (N=40) P value
OR time (min) 96 (48-200) 89 (30-249) 0.32
Blood loss (ml) 25 (5-200) 100 (5-400) 0.006
Length of stay (days)
4 (2-7) 7 (4-25) 0.002
Complications n(%)
6 (15%) 10 (25%) NS
Karakousis G, et al. Ann Surg Oncol. 2011 Jan 5. [Epub ahead of print]
Median follow up of 34 months, 1 recurrence in each group
Cases
GIST
Case 1: Laparoscopic wedge resection
VIDEOClear margin2.4 cm tumor12 mitoses / 50 HPF
Adjuvant gleevecLife long surveillance
GIST
Case 2: Distal duodenal lesion
GIST
Case 3: Primary - untreated
• 45 yo healthy man
• Symptoms• Vague abdominal pain x 6 months
• Weight loss, 20 lbs
• Exam• Left upper quadrant mass
• Evaluation• EGC
• CT (20 cm mass) and biopsy-proven GIST
GIST
Case 3: Primary - untreated
LIVER
SPLEENSTO
MACH
GIST
Case 3: Primary - untreated
GIST
Case 3: Primary - untreated
GIST
Case 3: Primary - untreated
• Organs resected• Total gastrectomy• Partial hepatectomy
• Pathology• 15 cm• High grade• Negative margins
• Additional treatment• 6 months gleevec• Noncompliant due to nausea
• Follow up• Dead of disease at 2 years
GIST
Case 4: Primary - pretreated
• 60 yo healthy man
• Symptoms• Vague abdominal pain x 6 months
• Weight loss, 25 lbs
• Exam• Left upper quadrant mass
• Evaluation• EGC
• CT (20 cm mass) and biopsy-proven GIST
GIST
Case 4: Primary - pretreated
• Surgical evaluation
• Deemed unresectable
LIVERSPLEEN
STOMACH
PANCREAS
COLON
GIST
Case 4: Primary - pretreated
• Medical therapy
• PET scan
• 6 months STI571
• Repeat scans
GIST
Case 4: Primary - pretreated
GIST
Case 4: Primary - pretreated
• Organs resected
• Partial gastrectomy
• Partial colectomy
• Pathology
• 21 cm
• High grade with significant necrosis
• 20% viable tumor remaining
• Negative margins
• Additional treatment
• Gleevec for 2 years
• Follow up:• Currently NED at 5 years
GIST
Case 5: Recurrent - symptomatic
• 63 yo woman
• 1998, explored for presumed leiomyosarcoma of uterus
• At operation, found to arise from stomach
• Final diagnosis, leiomyosarcoma
• Next presentation
• 2003, developed abdominal bloating and malaise
GIST
Case 5: Recurrent - symptomatic
GIST
Case 5: Recurrent - symptomatic
• Treatment course
• Received 4 months of gleevec
• Poor response on PET and no clinical improvement
• Admitted with malnutrition, shortness of breath and hypoglycemia
• Surgical consultation
• Palliative resection offered
GIST
Case 5: Recurrent - symptomatic
Front view Side view (looking left)
GIST
Case 5: Recurrent - symptomatic
HEAD
LIVER
GIST
Case 5: Recurrent - symptomatic
GIST
Case 5: Recurrent - symptomatic
GIST
Case 5: Recurrent - symptomatic
GIST
Case 5: Recurrent - symptomatic
• Organs resected• Partial colectomy
• Pathology• 44 cm mass• Additional foci• High grade
• Additional treatment• 8 months of adjuvant gleevec• 8 months of second-line therapy
• Follow up• Progression of disease
GIST
December 2005
GIST
December 2005
GIST
December 2005
GIST
Case 5: Recurrent - symptomatic
GIST
December 2005
GIST Summary
• CD117 positive mesenchymal tumors of the GI tract
• Low (60%) vs. high (40%) risk for metastasis and recurrence
• Optimal therapy is complete resection, possible in 50% at dx
• Standard chemotherapy and radiotherapy are ineffective
• Imatinib mesylate is effective and safe for adjuvant therapy of Kit–positive GIST and can be used preoperatively as well
• Laparoscopic resection may be preferred for small to medium primary gastric GIST over the open approach
GIST GISTResectable Unresectable
Complete Resection Gross Residual DiseaseGleevec
Tumor Progression
Gleevec dose escalationOr consider 2nd line Tx
Clinical Response
Re-evaluate Resectability
Resectable
Resection +/-Adjuvant Gleevec
Unresectable
MaintenanceGleevec
High RiskLow Risk
Observation Gleevec, at least 1 year
GIST
Thank you
?
GIST
DeMatteo RP, et al. ASCO 2008
GIST
At: http://www.acosog.org/studies/synopses/Z9000_Synopsis.pdf.
Phase II Trial (ACOSOG Z9000): Study Design (cont’d)
Complete resection of high-risk primary GIST
Imatinib mesylate(400 mg/dfor 1 year)
FollowforOS
GIST
DeMatteo RP, et al. ASCO 2008
GIST
DeMatteo RP, et al. ASCO 2008
GIST
DeMatteo RP, et al. ASCO 2008
GIST
DeMatteo et al., ASCO 2007
GIST
First GIST Case Study: Proof-of-Concept
• 50-year-old woman with a large abdominal mass
• Resection of primary tumor and omental metastases
• Multiple subsequent resections
• Postsurgical treatment:
• 4-agent chemotherapy (MAID)
• IFN- and thalidomide
• No clinical response
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
GIST
First GIST Case Study: Proof-of-Concept
Purpose/Dosage – Exploratory study in GIST
– 400mg/day orally
Clinical response – Total tumor size decreased by>75% at 8-month follow-up
– Excess metabolic activitydisappeared (PET scan)
– Tumor biopsies showedhistologic evidence of myxoiddegeneration and lack of mitoticactivity
Adverse effects – Mild nausea and increasedfrequency of bowel movements
Joensuu H et al. N Engl J Med. 2001;344:1052-1056.
GISTGIST: Recurrence-Free Survival Following Surgical
Treatment of Primary GIST
• Recurrence-free survival is predicted by tumor size and mitotic index
Singer et al. J Clin Oncol. 2002;20:3898.
0
0.25
0.50
0.75
1.0
0 20 40 60 80
<5 cm
5-10 cm
>10 cm
P=0.03
Months
Rec
urr
ence
-fre
e su
rviv
al
0
0.25
0.50
0.75
1.0
20 40 60 80Months
3 mitoses/30 HPF
>3 to 15 mitoses/30 HPF
>15 mitoses/30 HPFP=0.0001
0 R
ecu
rren
ce-f
ree
surv
ival
GIST
Classification
• Variants
• Spindle cell (70%)
• Epithelioid cell (20%)
• Mixed (10%)
• Light microscopy
• Eosinophilic spindle or round cells
• Short fascicles or storiform growth pattern
• Indistinct cell borders
• Cystic stromal degeneration
• Stromal hemorrhage
• Skenoid fibers
Spindle
Mixed
GIST
Risk for recurrence
Mitotic index
Tumor size (cm)
Stomach Duodenum Jejunum Rectum
<5/50 HPF
2 0 0 0 0
>2 - <5 2 8 4 9
>5 - <10 4 NA 24 NA
>10 12 34 52 57
>5/50 HPF
2 0 NA 50 54
>2 - <5 16 50 73 52
>5 - <10 55 NA 85 NA
>10 86 86 90 71
Miettinen L, Lasota J. Semin Diagn Pathol. 2006;23:70-83.
GIST
Kit Mutation Status and Prognosis
• KIT mutations are the best predictors of clinical response to imatinib mesylate
• 3 prognostic groups can be defined
• KIT Exon 11—favorable response (PR 83.5%, n=85)
• KIT Exon 9—intermediate response (PR 47.8%, n=23)
• No kinase mutation or PDGFRA D842V—worst response (no PR, n=12)
Heinrich et al. J Clin Oncol. 2003;21:4342.
GIST Phase III Trial (ACOSOG Z9001): Study Design
Objectives: Primary: OS with imatinib mesylate in adjuvant setting relative to placebo
Secondary: Recurrence-free survivalSafety/efficacy in adjuvant setting
Treatment: Imatinib mesylate administered at 400 mg/d
Inclusion: 3 cm GIST Surgery within 70 days prior to registrationKIT-positive GISTImatinib mesylate–naive No prior adjuvant therapy
At: http://www.acosog.org/studies/synopses/Z9001_Synopsis.pdf.
GIST
Results Z9001
• Completed accrual in 2007
• Gleevec arm, N=359
• Placebo arm, N=354
• Median follow up of ~20 months
• Improved recurrence-free survival from 83% to 98% (HR 0.35% 95% CI 0.22-0.53)
DeMatteo R, et al. The Lancet. 2000;373: 1097-1104
GIST
Surgical Margins for Primary GIST
• R0 resection of disease is the goal
• Management of positive margins unclear
• Repeated resection of unclear value
• Role for adjuvant imatinib mesylate therapy being evaluated
• Lymphadenectomy is generally unnecessary
Demetri et al. JNCCN. 2004;21(suppl 1):S1.
GIST
High risk GIST
• Median time to recurrence is 7 months to 2 years
• Only 10% of patients remain disease-free after extended follow-up
• Investigational protocols are indicated to reduce the rate of recurrence following resection
• Recurrent disease should be treated as metastatic disease
DeMatteo et al. Hum Pathol. 2002;33:466.Buemming et al. Proc Am Soc Clin Oncol. 2003;22:818. Abstract 3289.Ng et al. Cancer. 1992;69:1334.
Case 5: Recurrent - symptomatic
• Surgical evaluation
• Contemplated resection for recurrent leiomyosarcoma
• Referred to surgical oncologist
• Repeat biopsy CD117 postive
• Referred for gleevec therapy
GIST