In 2001 the National Institutes of Health in the USA held a conference of experts to discuss GIST and its diagnosis and treatment. One scheme for predicting the risk of recurrence or metastasis of a surgically resected primary GIST was developed by consensus at this meeting and was published by Fletcher et al (2002). This scheme is shown as Table 2. Note that this scheme does not provide a strict separation of benign versus malignant GIST. Occasionally even very small GIST of low malignant potential do recur or metastasize years after being surgically resected. Also note that this scheme does not apply to GISTs that are already metastatic at the time of diagnosis. There is general agreement that even after apparently complete removal of metastatic GIST, recurrence is extremely likely.

The prediction scheme shown as Table 2 has received support from subsequent population studies of primary GIST recurrence. Nilsson et al (2005) gathered data for every instance of KIT-positive GIST in a region of Sweden over the years from 1983 to 2000. They documented no instances of recurrence in the very low risk group, whereas the percentages of cases with recurrence or metastasis were 2.4% in the low risk group, 1.9% in the intermediate group, and 62.5% in the high risk group. A very similar study was carried out in Iceland for all GISTs diagnosed in the years 1990-2003 (Tryggvason et al, 2005), including 53 KIT-positive GISTs. No recurrences were seen in the very low or low risk categories. 20% of patients in the intermediate risk category experienced recurrence, as did 46% of patients in the high-risk category. Nakamura et al (2005) followed 80 cases of GIST and found that 4.5% of intermediate-risk cases recurred, compared to 38.5% of high-risk category cases. These studies confirm the value of the NIH (Fletcher et al, 2002) risk scheme. Numerous other studies not directly evaluating the scheme have nonetheless verified that tumor size and mitotic rate (or an alternative proliferation index) are good predictors of recurrence or metastasis.

Some research indicates that the mitotic rate may be more influential in predicting recurrence than tumor size.  Bearzi et al (2006) reviewed 158 cases of GIST seen in a single pathology lab from 1990-2003. Results did support the Fletcher (2002) NIH consensus risk categories: none of the very-low or low-risk patients died of GIST, and only 2 of 32 with intermediate risk (6.2%). In the high-risk category 49% evidently achieved curative surgery, while 39% died of GIST (remember, this is mostly pre-imatinib!) and apparently the remaining 12% are alive on imatinib (apparently prescribed after recurrence). They found that tumor size was much less predictive of outcome than the mitotic count. Only 12% of patients with a mitotic count over 10/50 HPF remained disease-free after surgery, and all patients with a mitotic count over 20/50 HPF experienced recurrence.  The largest study available of gastric GISTs (Miettinen et al, 2004) had also previously suggested that mitotic count has a greater prognostic influence than tumor size.  Although 86% of tumors > 10 cm with >5 mitoses / 50 HPF did metastasize, only 11% of tumors > 10 cm with < 5 mitoses / 50 HPF metastasized. Miettinen et al also reasoned that when data are analyzed by mathematical regression models, tumor size may appear to show greater predictive value because mitotic count reaches a “saturation point” when counts exceed 10/50 HPF.  In summary, the pathology report provides GIST patients and their physicians the best information available to assess risk of recurrence after a GIST is surgically removed. If the combination of size and mitotic count places a tumor in the high-risk category, the mitotic count may be the more indicative variable.

Numerous authors have observed that the risk of recurrence appears to vary by the anatomical location of the primary GIST, with GISTs of the stomach being less aggressive than tumors in other locations, especially the small intestine. Miettinen et al (2002) proposed a risk scheme that separates risk for gastric versus intestinal tumors, and this is shown as Table 3.

Other tumor characteristics often found to be associated with a greater risk of malignancy include the presence of necrosis, high cellularity, infiltration of adjacent structures, mucosal invasion, and rich vascularity (plenty of blood supply to the tumor). Tumors with exon 9 mutations appear to be more aggressive than those with exon 11 mutations (Lasota et al, 2003; Antonescu et al, 2003).

Incomplete resection of the primary tumor is clearly associated with a much higher risk of recurrence. However, resection of all gross tumor may be adequate, without obtaining wide surgical margins to eliminate microscopically detectable tumor cells (NCCN Soft Tissue Sarcoma Guidelines, 2005). Tumor rupture (whether during surgery or spontaneously before the tumor has even been detected or diagnosed) greatly increases the probability of recurrence because the spilled cells can seed the abdominal cavity.

Note that the results of recurrence studies are strongly influenced by the time period for which patients are followed to identify recurrence or metastasis. Although many tumors reappear or metastasize within two years of the surgical resection of the primary GIST, there are documented cases of metastasis after 10-20 years. Therefore, given longer follow-up, the risk would be found to be greater.

Genetic factors related to prognosis

Numerous papers have explored single aspects of gene expression that may be related to the aggressiveness of GISTs, but there has been no coherent program of research to evaluate these factors on large numbers of cases. Therefore, it is difficult to predict which ones may be of practical value. Many GISTs show other gene abnormalities beyond the mutation of c-kit or PDGFRA. Expression of telomerase is also associated with greater aggressiveness. Loss of expression of genes 14q, 22q, 1p, and 9p has been correlated with poorer prognosis. However, there is too little information at present to warrant testing of such characteristics in individual cases.

Some recent information indicates that the exact mutation found in a GIST may predict its chance of recurrence. Emile et al (2004) and Martin et al (2005) identified specific types of mutations within c-kit exon 11 that were associated with metastasis.   Several papers have found that patients with deletions within exon 11 (in contrast to substitutions or duplications) have a poorer prognosis (greater probability of recurrence or metastasis) than other GIST patients (Singer et al, 2002; Wardelmann et al, 2003; Andersson et al, 2006; Cho et al, 2006).  If these sorts of results are confirmed and expanded, they could provide a rationale for identifying patients who need closer monitoring, or perhaps adjuvant drug treatment (drugs prescribed post-surgery to prevent recurrence, in contrast to drugs prescribed after the appearance of metastasis).