Elsevier

Human Pathology

Volume 39, Issue 10, October 2008, Pages 1411-1419
Human Pathology

Progress in pathology
Risk stratification of patients diagnosed with gastrointestinal stromal tumor

https://doi.org/10.1016/j.humpath.2008.06.025Get rights and content

Summary

Accurate risk stratification of gastrointestinal stromal tumors (GISTs) has become increasingly important owing to emerging adjuvant systemic treatments. All GISTs have been considered to have some malignant potential, but this hypothesis is now seriously challenged by studies indicating that microscopic gastric GISTs that are common in the general population probably have little or no malignant potential. The National Institutes of Health (NIH) consensus classification system, based on tumor size and mitotic count, is commonly used to assess patient prognosis after surgical resection. Large retrospective cohort studies from several countries now uniformly indicate that the NIH classification carries substantial prognostic value. In particular, patients with high-risk GIST (approximately 44% of all) have substantially poorer outcome than those with intermediate-risk (24%) or low/very low-risk GIST (32%), whose survival is not markedly inferior to that of the general population in some studies. Gastric GISTs (approximately 58% of all GISTs) have a lower risk of recurrence than nongastric tumors of the same size and mitotic count, and tumor rupture confers clearly increased risk. These 2 important risk stratification factors are not considered in the NIH classification. Patients with certain nongastric tumors (2.1-5 cm and >5 mitoses per 50 high-power fields or 5.1-10 cm and ≤5 per 50 high-power fields) and those with tumor rupture are proposed to be included in the NIH high-risk category. High-risk patients defined by the proposed modified system have more than 15% to 20% risk of disease recurrence. The proposed system, if validated, may be useful in identifying which patients might potentially benefit from adjuvant therapy.

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with an annual incidence of approximately 7 to 19 cases per million [1], [2], [3]. They may arise anywhere along the gastrointestinal tract, but they are most commonly found in the stomach and small intestine, and they may rarely arise at extragastrointestinal sites such as the omentum or mesentery [4]. Activating mutations of KIT and less commonly PDGFRA, which encode the stem-cell factor receptor (KIT) and platelet-derived growth factor receptor α (PDGFRα) tyrosine kinases, respectively, are believed to be pivotal in the molecular pathogenesis [4]. Such activating mutations cause constitutive activation of the tyrosine kinase activity of these receptors and consequently activation of downstream signaling pathways.

The malignant potential of GISTs varies from virtually benign tumors to aggressive sarcomas. Some patients are at significant risk for tumor recurrence and progression to metastatic disease even after complete excision of their tumors [4]. Patient prognosis is commonly stratified according to the National Institutes of Health (NIH) consensus classification system based on tumor size and mitotic count [5]. Since publication of the NIH classification, additional prognostic factors have been proposed in the medical literature, which may further improve risk stratification. The need for accurate risk stratification has become increasingly important since the introduction of imatinib—a low-molecular-weight tyrosine kinase inhibitor that blocks the kinase activity of both KIT and PDGFRα [6].

Imatinib is now being explored as adjuvant therapy in patients with primary resectable GIST because clinical trials in patients with unresectable or metastatic GISTs found that imatinib substantially improves survival in advanced GIST and is generally well tolerated [7], [8]. Preliminary results from the American College of Surgeons Oncology Group Z9001 trial—a large, randomized, double-blind, phase 3 study of patients with KIT-expressing GISTs 3 cm or more in size—showed that imatinib 400 mg/d given for 12 months postoperatively improved 1-year recurrence-free survival (RFS) compared with placebo (97% versus 83%; P < .00001) [9]. Accurate risk stratification is crucial for the selection of patients who are most likely to benefit from adjuvant imatinib therapy, initially in clinical trials and ultimately in clinical practice. This article reviews risk stratification in resectable GISTs and illustrates how recent findings may not only improve risk assessment but also identify patients who are potentially most likely to benefit from adjuvant therapy.

Section snippets

NIH consensus classification system

The NIH consensus classification system—based on a GIST Workshop convened by the NIH in April 2001—stratifies risk of an aggressive clinical course based on tumor size and mitotic count (Table 1) [5]. It does not attempt to distinguish between benign and malignant tumors, given that even very small tumors and those with low mitotic counts will occasionally metastasize, and even small GISTs were thus considered to have some malignant potential. Accordingly, patients with very small tumors less

Prognostic factors not included in the NIH consensus classification

Patients presenting with symptoms may have a poorer outcome than those without symptoms. Hassan and colleagues found that a symptomatic presentation was independently associated with poor 5-year disease-free survival (DFS) (HR, 2.5; 95% CI, 1.1-6.0; P = .04) and disease-specific survival (HR, 3.1; 95% CI, 1.2-7.9 to 5; P = .02) in a cohort of 146 patients who had complete surgical resection of a localized GIST [28]. Other independent prognostic factors in this cohort were high-risk group on NIH

Armed Forces Institute of Pathology series of GISTs

A few recent studies that have evaluated large patient cohorts provide a potential to expand upon the NIH classification and further refine risk stratification. The Armed Forces Institute of Pathology (AFIP) series of 1765 gastric GISTs [32] and 906 GISTs of the jejunum and ileum [33] are the largest to evaluate how clinicopathologic features of these tumors influence prognosis. In the series of gastric GISTs, full long-term follow-up data were obtained for 1074 patients, of whom 511 patients

Other large cohorts of patients with GIST

The prognostic value of the NIH consensus classification has been evaluated in 6 large (>100 cases) retrospective cohort series with information available on the numbers of patients in each of the prognostic risk category (Table 3) [1], [2], [27], [28], [35], [36]. Most GISTs in these series had their origin in the stomach (889/1530, 58.1%), and 39.9% were intestinal GISTs. The single largest NIH risk category in these studies was high-risk GISTs (44.0%), followed by very low/low-risk GISTs

Proposal for risk stratifying patients with GISTs

The use of tumor size as the sole criterion of risk stratification is unlikely to be a sufficiently sensitive prognostic parameter for selecting patients who might benefit from adjuvant systemic treatments. Such a policy would likely result in overtreatment of patients with gastric tumors with low mitotic counts and undertreatment of patients with small intestinal GISTs with a high cell proliferation rate.

Tumor size and mitotic count are well-documented prognostic factors in resectable GISTs,

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    This study was supported by funding from the Academy of Finland, Research Funds of Helsinki University Central Hospital, Sigrid Juselius Foundation, and Cancer Society of Finland.

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