Prognostic Value of<i>KIT</i>Mutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors

Singer, Samuel; Rubin, Brian P.; Lux, Marcia L.; Chen, Chang Jie; Demetri, George D.; Fletcher, Christopher D.�M.; Fletcher, Jonathan A.

doi:10.1200/jco.2002.03.095

Cited by 405 publications

(278 citation statements)

References 27 publications

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“…There is a strong need for a practical and reliable classification system that can be used to predict the clinical course of GIST patients and facilitate the design of treatment regimen. On the basis of previous investigations and our preliminary work, [10][11][12][13][14][15][16][17][18] we collected the pathological and clinical data of a large number of GIST patients and assessed a simple and new grading and staging system. Patients from multiple hospitals were analyzed because it is expected to be more likely free of selection bias, which could occur in different hospitals or treatment trials.…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, some patients with malignant GIST are highly aggressive, developing recurrence within short time after surgical removal of the primary tumor, whereas others can be treated effectively by surgical resection alone or had a long latency to develop recurrence. Many investigators made efforts to grade [10][11][12][13][14][15] and/or stage GISTs. 11,[16][17][18] On the basis of these previous reports and our preliminary study, we selected 12 parameters that not only had predictive value for malignancy, but also had value to stage and grade GISTs effectively.…”

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confidence: 99%

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Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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Tumor stage and grade for gastrointestinal stromal tumors are poorly defined. To develop a better evaluation system, we assessed 12 clinical and pathological parameters in 613 patients with follow-up information. These parameters were classified into two gross spread parameters including liver metastasis and peritoneal dissemination, five microscopic spread parameters including lymph node metastasis, vascular, fat, nerve and mucosal infiltration, and five histological parameters including mitotic count Z10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern and severe nuclear atypia. The 5-year disease-free survival and overall survival of 293 patients without any of these predictive parameters of malignancy were 99% and 100%, respectively. They were regarded as nonmalignant and further evaluations on the stage and grade of these tumors were not performed. At least one and at most seven predictive parameters of malignancy were identified in 320 patients. For these patients, the 5-year disease-free survival and overall survival rates were 44% (mean 6.7 years) and 60% (mean 9.3 years), respectively. The disease-free survival showed significant difference between patients with and without gross spread (Po0.0001), with and without microscopic spread (P ¼ 0.0009). Disease-free survival and overall survival were associated with the number of predictive parameters of malignancy in patients without gross spread (Po0.0001 for both disease-free survival and overall survival), but not in patients with gross spread (P ¼ 0.882 and 0.441, respectively). Malignant gastrointestinal stromal tumors could be divided into clinical stage I and II based on the absence and presence of gross spread, respectively. The degree of malignancy of patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy regardless of the number of parameters. We found that the clinical stage and grade were strongly associated with prognosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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“…The deletions are associated with a shorter progression-free and overall survival in comparison with the other exon 11 mutations. [12][13][14][15][16][17][18] In particular, deletions involving codons 557 and/or 558 are associated with malignant behavior. [19][20][21] Aside from exon 11 mutations, between 7 and 10% of GISTs have a mutation in an extracellular domain encoded by exon 9.…”

Section: Kitmentioning

confidence: 99%

“…37 PDGFRA is activated in GISTs harboring mutations in the juxtamembrane domain (exon 12), the ATP-binding domain (exon 14), or the activation loop (exon 18) ( Figure 2 and Table 2). Consistent with their extensive functional overlap, KIT and PDGFRA mutations are mutually exclusive in GISTs.…”

Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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“…The presence of an epithelioid/mixed morphology/ component in GISTs was associated with malignant behavior in GISTs in several studies. 6,[9][10][11][12] On the other hand, PDGFRA-mutated epithelioid GISTs frequently exhibit a less aggressive behavior. 7,8,[13][14][15] Recently, we identified a morphological shift from spindled to epithelioid phenotype in GISTs that were composed of well-circumscribed spindled and epithelioid components.…”

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confidence: 99%

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

et al. 2011

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In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray. Independent of their anatomical localization, the majority of KIT-mutated GISTs displayed a pure spindled phenotype (72%), with the remaining tumors showing an epithelioid/mixed growth pattern. In KIT-mutated GISTs from the stomach, the occurrence of an epithelioid/ mixed growth pattern was significantly correlated with larger tumor diameters (P ¼ 0.005), higher mitotic counts (P ¼ 0.0001), high-risk category (P ¼ 0.001), higher expression of the G2-phase cell-cycle marker cyclin B1 (P ¼ 0.04), higher expression of the G1 to M-phase proliferation marker Ki67 (P ¼ 0.02) and a significantly shorter disease-free survival (P ¼ 0.003) compared with tumors with pure spindled morphology. In contrast, there were no significant differences between pure spindled and epithelioid/mixed GISTs from the small/large bowel. Our findings indicate that the epithelioid/mixed phenotype in KIT-mutant gastric GISTs represents a secondary tumor growth pattern associated with tumor progression and adverse outcome, probably through accelerated G1/S-phase restriction point passage.

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Prognostic Value ofKITMutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors

Cited by 405 publications

References 27 publications

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Gastrointestinal stromal tumors: what do we know now?

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

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