Prognosis in GIST

Gastrointestinal stromal tumors (GISTs) span a wide spectrum of malignant potential. When a GIST is surgically removed (resected), both physicians and patients want to predict whether the surgery was curative versus the alternative that GIST will reappear later. There is general agreement that a complete R0 resection (indicating clear margins) offers the hope of a cure in primary GIST. Although leaving microscopic evidence of tumor cells on the margins (an R1 resection) may sometimes be sufficient to prevent recurrence, an incomplete resection leaving visible tumor behind (an R2 resection) is not curative. For more about resection status, see the glossary on the GSI website, where other terms briefly defined in this article are explained in more detail. After a complete R0 resection of a primary GIST, the prognosis or recurrence or metastasis is usually assessed using a table of risk categories created during a National Institutes of Health consensus conference in 2001 (Fletcher et al, 2002). Tumors that have already metastasized at the time of diagnosis are not categorized using this scheme; patients with metastatic GIST are usually treated with imatinib (also known as Gleevec® and Glivec® and, in earlier publications, as CGP57148B or STI571).

The NIH risk table uses the maximum dimension of the tumor, plus the mitotic count, to predict risk of either recurrence (regrowth in essentially the same location) or metastasis (development of tumors in new locations, usually the liver or peritoneum for GIST). Tumor size is measured in centimeters (cm) on the longest axis. Mitotic rate is a measure of tumor cell proliferation (cell division to create new cells, indicating the rate of growth of the tumor). Mitotic count is assessed by a pathologist while viewing slides of a tumor under a microscope. The pathologist counts the number of mitotic figures (cells undergoing division) per 50 high-power fields (HPF) under the microscope and reports the count per 50 HPF. A high-power field is the area of a slide of tumor sample that can be seen under a microscope using high magnification; this is not a standardized exact area, but Fletcher et al (2002) state that the measure is still useful even though "there are no agreed-on definitions". For example, a mitotic count of 10/50 HPF would indicate 10 mitoses counted in 50 fields. Sometimes only 10 fields are counted; in this case the ratio seen in 10 fields can be converted to that expected in 50 fields. For example, 1/10 HPF would be equivalent to 5/50 HPF.

Data published in the past five years support the usefulness of the risk categories (very low, low, intermediate, and high) from the NIH consensus risk scheme. A dataset from Sweden (Nilsson et al, 2005), including all KIT-positive GISTs in a region of Sweden from 1983-2000, provides a prospective follow-up of all cases. KIT-positive GISTs are the approximately 95% of GISTs that stain positively for a protein called KIT (also called CD-117), which is the receptor for the growth factor known as stem cell factor. Mutations in KIT result in uncontrolled tumor growth in most GISTs. Even KIT-expression-negative GISTs may harbor KIT mutations. However, a few GISTs show mutations in the similar growth factor receptor PDGFRA (platelet derived growth factor receptor alpha), and a few show no mutations in either KIT or PDGFRA and are called "wild-type". The authors 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-risk 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, but 20% of patients in the intermediate-risk category experienced recurrence, as did 46% of patients in the high-risk category. The Swedish and Icelandic datasets are particularly valuable because they have no selection bias except the exclusion of KIT-expression-negative cases. 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 risk scheme.

This year two more papers have appeared with more analyses of the Swedish population-based dataset: a surgery analysis by Bumming et al (2006) and a mutation analysis by Andersson et al (2006). Excluding GISTs found at autopsy, there were 259 GISTs found based on either patient symptoms (199 cases) or incidentally during other surgeries (60 cases). Of the 199 symptomatic cases, 29 (14.6%) were metastatic at discovery and were excluded from further prognosis analysis. In the high-risk group, 48 of 60 patients achieved complete R0 resection, and 30 of these 48 (62.5%) developed recurrence or metastasis, while 37.5% remained with no evidence of disease. The Nilsson et al (2005) paper included an equation to predict risk of recurrence for individuals using tumor size and Ki-67 proliferation index (another indicator of proliferation that uses a percentage of cells in any non-resting state rather than a count of actual mitoses). Bumming et al refined this predictive equation by including the mutation status of each tumor (as described by Andersson et al). Mutations may be detected in different exons of a gene. Exons can be thought of as sections of the gene that contain the instructions for building a particular physical part of the complete protein encoded by the gene. If a certain KIT exon is mutant, the section of the KIT receptor it codes for will be incorrectly formed in the cell. When the exon location and type of mutation were included as inputs to the prediction equation, Bumming et al found that the presence of a deletion mutation within exon 11 of KIT was predictive of a poorer prognosis than other types of exon 11 mutations (substitutions or duplications), and a poorer prognosis than mutations in other KIT exons, mutations in PDGFRA, or wild-type KIT and PDGFRA (no detectable mutations). About 60% of exon-11 mutations in this series were deletions, the other 40% being duplications or substitutions. 49% of exon 11 deletions fell into the high-risk group. 31% of all exon 11 deletions (not limited to the high-risk ones, but mostly in the high-risk group) developed recurrent disease. In contrast, the percentages of recurrent disease for other groups (all risk categories) were 17% for tumors with no KIT mutations (wild type or PDGFRA-mutant), and 13-18% for tumors with other KIT mutations (in other exons or duplications or substitutions in exon 11).

Another new paper by Cho et al (2006) on 56 Japanese patients with gastric GISTs also found that exon-11 deletions were associated with a poorer prognosis. 25% of exon-11-deletion patients developed liver metastases, compared to 0-6% of other mutation categories, and their survival was poorer. Earlier publications had also indicated a poorer prognosis for patients with KIT exon 11 deletions: Wardelmann et al (2003); Corless et al (2004); Miettinen et al (2004); Martin et al (2005).

In short, there is a growing body of evidence that the specific mutation status can contribute prognostic information in GIST. Mutation testing for high-risk tumors may therefore be prudent.

In the absence of mutation testing, the mitotic count may provide the best prognostic clues according to a recent study by Bearzi et al (2006). The authors 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 (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.

Some slow-growing tumors can reach large sizes without becoming aggressive.Bearzi et al describe two cases in point:

1. An 11-cm gastric GIST with a mitotic count of zero was removed and had not recurred after five years.
2. A 14-cm small intestinal tumor that had infiltrated the bladder, with a mitotic count of 3/50 HPF, had not recurred in five years after resection of all tumor and the affected part of the bladder.

Data such as these can indicate which patients may benefit most from adjuvant imatinib after successful surgery, to prevent recurrence. Because the Swedish studies used the Ki-67 index (not mitotic rate) as the measure of tumor cell proliferation, it is not possible to make a direct comparison from the Bearzi et al study to the Swedish dataset. However, Nilsson et al (2005) did show the following:

• If you hold tumor size equal, then risk increases as the Ki-67 proliferation index increases.
• If you hold Ki-67 proliferation index constant, then risk increases as tumor size increases.

Examination of the graphs illustrating the preceding statements in the Nilsson et al paper shows that there is a wider divergence in survival as a function of proliferation index than there is for tumor size. For example, the prediction curve for 5-cm tumors shows over 60% survival at ten years if the proliferation index is 5%, over 50% survival if the proliferation index is 10%, but only about 25% if the Ki-67 index is 25%. In contrast, predicted 10-year survival for 1% Ki-67 index decreased from over 70% for tumors of only 5 cm to about 50% for tumors of 15 cm.

The largest study available of gastric GISTs (Miettinen et al, 2004) had 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. Finally, mutation analysis can add prognostic information, as well as being relevant to the tumor’s response to imatinib.