Prologue
Diagnosis
Radiology
Histology
Techniques for histological diagnosis
Pathological characteristics
Macroscopic characteristics
Microscopic characteristics
Immunohistochemistry
Differential diagnosis
Kit-negative GIST
Final recommendations
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Pathologic diagnosis is based on both unique microscopic features and ancillary techniques (CD-117, CD34, actin, desmin, S-100 and ki-67), which are very important to confirm diagnosis.
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The pathology report must include tumor size; number of mitoses per 50 HPF (10 mm2) counted in the most active regions; and margins status.
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It is advisable to refer the complex or unusual cases to experienced centers.
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Regarding tumors with typical morphology GIST, an extended phenotype of DOG1 as well as KIT and PDGFRA gene mutation analysis is required.
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Albeit optional, it is convenient to include the risk group separated by site. Table 1 (Miettinen et al.) [23] and histologic grading defined exclusively by the number of mitosis (low grade ≤5/50HPF, high grade >5/50HPF).Table 1Primary gastrointestinal stromal tumors (GIST) risk assessment guidelinesTumor parametersRisk of progression* (%)Mitotic indexSizeStomach***Small bowel***≤5 per 50 high-power field (HPF)≤2 cmNo (0 %)No (0 %)>2–≤5 cmVery low (1.9 %)Low (4.3 %)>5–≤10 cmLow (3.6 %)Moderate (24 %)>10 cmModerate (10 %)High (52 %)>5 per 50 HPF≤2 cmNo**High**>2–≤ 5 cmModerate (16 %)High (73 %)>5–≤10 cmHigh (55 %)High (85 %)>10 cmHigh (86 %)High (90 %)
Molecular diagnosis
Spectrum of mutations in GIST
KIT mutations
PDGFRA mutations
GIST wild type
Kit-negative GIST
Syndromes associated with GIST
Final recommendations
Predictive factors in locally advanced or metastatic disease
Genotype correlation in primary disease with therapeutic results with imatinib for first line
Genotype correlation in primary disease with therapeutic results imatinib dosage
Primary genotype correlation with therapeutic results with sunitinib as second-line therapy
Secondary genotype correlation with therapeutic results for sunitinib
Mechanisms of resistance to imatinib
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Acquisition of secondary KIT mutations
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KIT gene amplification
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Activation of alternative signaling pathways
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Functional resistance due to KIT or PDGFRA activation in absence of secondary mutations.
Final recommendations
Treatment
Localized disease
Surgery for localized disease
Prognostic factors after surgery in localized GIST
Size*
| Mitotic index (50 HPF)** | |
---|---|---|
Very low-risk | <2 cm | ≤5 mitosis |
Low-risk | 2–5 cm | ≤5 mitosis |
Intermediate-risk | ≤5 cm | 6–10 mitosis |
5–10 cm | 5 mitosis | |
High-risk | >5 cm | >5 mitosis |
>10 cm | Any number of mitosis | |
Any size | >10 mitosis |
Size | Mitotic index (50 HPF)*
| Location | |
---|---|---|---|
Very low risk | 2–5 cm | ≤5 mitosis | Gastric |
Low risk | >5 years ≤10 cm | ≤5 mitosis | Gastric |
2–5 cm | ≤5 mitosis | Intestinal | |
Intermediate risk | >10 cm | ≤5 mitosis | Gastric |
>5 years ≤10 cm | ≤5 mitosis | Intestinal | |
2–5 cm | >5 mitosis | Gastric | |
High-risk intestinal | 2–5 cm | >5 mitosis | Intestinal |
>10 cm | ≤5 mitosis | Intestinal | |
>5 years ≤10 cm | >5 mitosis | Gastric | |
> 10 cm | >5 mitosis | Gastric | |
>5 years ≤10 cm | >5 mitosis | Intestinal | |
>10 cm | >5 mitosis | Intestinal |
Final recommendations
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We recommend the use of the risk group classification proposed by Miettinen as it is the best at identifying low, intermediate and high-risk populations. Spontaneous or intraoperative capsule rupture should be considered as a very poor prognostic factor.
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Deletion type of mutations affecting codons 557 and 558 confers a risk for recurrence regardless of its previous classification, according to our experience. The risk is greatest within the first 30 months after surgery and then drops drastically. Nevertheless, results from other prospective studies are needed in order to assess the value of this variable.
Adjuvant treatment
Imatinib trials overview
Special cases
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Capsule break: These are generally accepted as disseminated patients given that 100 % will relapse, at least on a peritoneal level. Therefore, imatinib administration is recommended as advanced disease setting.
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Specific genotypes: Adjuvant imatinib is not recommended in patients with D842 V PDGFRα mutation given its known resistance to it. There is no consensus regarding the benefit of a daily dose of 400 mg of imatinib for carriers of an exon 9 mutation in the KIT gene. The efficacy of a daily dose of 800 mg of imatinib was extrapolated from the evidence of disseminated disease. Nonetheless, this scenario has not been proven in clinical trials and therefore has not been approved for adjuvant treatment. Survival in patients with wild type does not seem to increase with the use of adjuvant imatinib, and thus, there is still controversy over imatinib administration and each case must be considered individually.
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Patients with R1 surgery: There is no evidence confirming the benefit of adjuvant imatinib in low-risk patients with affected microscopic margins. Surgical reexcision could be considered for these cases (see surgical section).
Final recommendations
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High-risk patients: 3 years of adjuvant treatment with imatinib is recommended.
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Low-risk patients: adjuvant treatment is not indicated.
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Intermediate-risk patients: currently, there is not enough scientific evidence to support adjuvant treatment with imatinib. For uncertain cases, it is important to carry out an assessment of risk of recurrence and properly classify them by using modified classification tools (modified Miettinen classification of Joensuu H).
Advanced disease
Treatment of unresectable or metastatic disease
Dose and efficacy of imatinib treatment
Predictive value of genotype for imatinib efficacy
European phase I/II (n = 37) | B2222 phase II (n = 127) | European/Australian Asian phase III (n = 363) | North American SWOG S0033 phase III (n = 324) | Weighted average | ||
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% (n) | % (n) | % (n) | % (n) | % (n) | ||
Objective response
a
| ||||||
KIT exon 11 | 83 (24) | 83b (85) | 70b (248) | 67b (211) | 71 (568) | |
KIT exon 9 | 25 (4) | 48 (23) | 35 (58) | 40 (25) | 38 (110) | |
No mutation | 33 (6) | 0 (9) | 25 (52) | 39 (33) | 28 (100) | |
Progressive disease
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KIT exon 11 | 4 % | 5 % | 3 % | 8 % | 5 % | |
KIT exon 9 | 0 % | 17 % | 17 % | 16 % | 16 % | |
No mutation | 33 % | 56 % | 19 % | 21 % | 23 % |
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Genotype is mandatory for treating advanced/metastatic GIST patients. Evidence II, A.
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Imatinib 400 mg/day is the recommended dose in first line in advanced/metastatic GIST. Evidence I, A.
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In exon 9 mutants, imatinib 800 mg/day is the recommended dose. Evidence III, A.
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In PDGFRA/KIT WT GIST is not clear enough that imatinib should be the standard.
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In imatinib-resistant D842 V mutant, alternative treatments other than imatinib could be advised (i.e., dasatinib). Evidence IV, B.
Practical issues on imatinib as first line in GIST
Treatment for patients with disease progression following imatinib failure
Response evaluation
RECIST | PET | Choi criteria | |
---|---|---|---|
Complete response (CR) | All lesions must disappear | Lack of FDG uptake | All lesions must disappear |
Unable to distinguish it from surrounding tissue | No new lesions | ||
Partial response (PR) | Decreasing size 30 % of sum of target lesions | Decreasing size 15–25 % of SUV after 1 cycle and more than 25 % after subsequent cycles | Decreasing size >10 % or decreasing density ≥15 % HU |
Stable disease (SD) | Between PR and PD | <25 % increase or SUV decreases <15 % | Does not fufil CR, PR or PD criteria |
No symptom deterioration due to tumor progression | |||
Progressive disease (PD) | Target lesions increase >20 % | SUV increases >25 % or new lesion uptake | Size increases >10 % without density decreasing |
New intratumoral nodules | |||
Size or tissue part of hypodense lesion increases |
Follow-up of patient diagnosed with gist
Localized resectable disease
Localized unresectable or metastatic disease
Special cases
Neoadjuvant and induction therapy
Final recommendations
Small GIST<2 cm
Focal progression
Final recommendations
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Systemic therapy should not be interrupted or replaced when progression is limited to a single or only a few focal points amenable to local treatment.
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Choice treatment for focal progression is maintenance of systemic therapy together with local control techniques appropriate for each case.