Prognosis for GIST (Risk of Recurrence or Metastasis)

Two “risk tables” discussed below are commonly used to predict the probability that gastrointestinal stromal tumor (GIST cancer) will recur after successful surgery to remove a primary GIST.  In addition, beginning in 2010 GIST can be “staged” using new staging criteria from the American Joint Committee on Cancer, as discussed after the risk tables.

NIH or Fletcher Risk Table

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.  It is frequently referred to either as the NIH risk table or as the Fletcher risk table.

This scheme does not provide a strict separation of benign versus malignant GIST. Experts prefer not to use the word “benign” for any GISTs.  Occasionally even very small GISTs of low malignant potential do recur or metastasize years after being surgically resected.

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.

Table 2. Risk of Aggressive Behavior in GISTs (from Fletcher et al, 2002, Human Pathology 33(5):459-65, used with permission of Elsevier)
Size (largest dimension) Mitotic Count
very low risk <2 cm <5 / 50 HPF
low risk 2-5 cm < 5 / 50 HPF
intermediate risk <5 cm 6-10 / 50 HPF
5-10 cm < 5 / 50 HPF
high risk >5 cm > 5 / 50 HPF
>10 cm any mitotic rate

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.

Miettinen & Lasota Risk Table for GIST

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 separated risk for gastric versus intestinal tumors.  More recently Miettinen and Lasota (2006) have refined their risk table based on followup information for over 1900 GIST patients over time.  Dr. Miettinen and Dr. Lasota are pathologists at the Armed Forces Institute of Pathology (AFIP) who have compiled the largest series of GISTs in the medical literature.  [For a Q&A piece by Dr. Miettinen and Dr. Lasota about their work, link to Gastrointestinal Stromal Tumor Pathology and Prognosis.]

The NIH table shown above as Table 2 was based on consensus professional opinion, but the table formulated by Miettinen and Lasota (2006) is based on actual data for over 1900 GIST patients, noting the percentages of patients in diferent categories (based on tumor location, size, and mitotic rate) who actually did develop recurrence or metastasis.  The new Miettinen & Lasota risk table is shown below as Table 3.

 

Table 3.  Rates of metastases or tumor-related death in GISTs by tumor location, grouped by Tumor Size and Mitotic Rate. Adapted from Miettinen and Lasota (2006), Seminars in Diagnostic Pathology, 23:70-83, used with permission of Elsevier.
Tumor Parameters Percent of patients with progressive disease during long-term follow-up and characterization of risk for metastasis
Group Tumor_Size_ Mitotic_Rate Gastric GISTs Jejunal and Ileal GISTs Duodenal GISTs Rectal GISTs
1 ≤2 cm

 

 ≤5–/–50–HPFs 0%
none		 0%
none		 0%
none		 0%
none
2 >2 cm ≤5 cm

 

 ≤5–/–50–HPFs 1.9%
very low		 4.3%
low		 8.3%
low		 8.5%
low
3a >5 cm ≤10cm ≤5–/–50–HPFs 3.6%
low		 24%
moderate		 34%
high ‡		 57%
high ‡
3b >10 cm ≤5–/–50–HPFs 12%
moderate		 52%
high
4 ≤2 cm >5 / 50 HPFs 0% † 50% † § 54%
high
5 >2 cm ≤5 cm >5 / 50 HPFs 16%
moderate		 73%
high		 50%
high		 52%
high
6a >5 cm ≤10cm >5 / 50 HPFs 55%
high		 85%
high		 86%
high		 71%
high ‡
6b >10 cm >5 / 50 HPFs 86%
high		 90%
high
† denotes tumor categories with very few cases

‡ Groups 3a and 3b, 6a and 6b are combined in duodenal and rectal GISTs
because of small number of cases.

§ No tumors of such category were included in the study.

NOTE that small intestinal and other intestinal GISTs show a markedly worse prognosis in many mitosis and size categories than gastric GISTs.

You can observe from Table 3 that the risk of recurrence is greater for non-gastric GISTs than for gastric GISTs of the same size and mitotic count.  DeMatteo et al (2008) evaluated data for 127 patients with primary GIST and confirmed the AFIP finding that tumor site (anatomical location) is an independent prognostic factor, along with tumor size and mitotic rate.

Goh et al (2008) applied the NIH/Fletcher risk criteria (Table 2), a modification of the NIH/Fletcher scheme, and the Miettinen and Lasota / AFIP criteria (Table 3) to the records for all the GIST patients treated in one hospital over many years.  The Miettinen and Lasota / AFIP criteria proved superior in predicting patient outcome.  Goh et al did note that there is a wide spread of recurrence rates within the AFIP high-risk group.  Goh et al demonsrated that it is useful for patient outcome prediction to add a “very high risk” group with tumor size > 10 cm and mitotic count > 5 per 50 HPFs.  That is to say, for patients with mitotic counts >5 per 50 HPFs, those with tumors between 5 and 10 cm had fewer recurrences than those with tumor size >10 cm.

 

NCCN Risk Table for GIST

The NCCN (National Comprehensive Cancer Network) GIST Task Force adopted the Miettinen and Lasota table in the 2007 and 2010 reports Optimal Management of Patients with GIST — Update of the NCCN Clinical Practice Guidelines. (Click the preceding title to download a pdf of this comprehensive report after completing a free registration.)  Therefore, the Miettinen and Lasota (or AFIP) scheme as shown in Table 3 and the equivalent NCCN adaptation shown as Table 4  are considered the best current methods for predicting GIST risk of recurrence.  

Table 4.  Risk classification for primary GIST by mitotic index, size, and tumor site. Adapted by NCCN from Miettinen and Lasota, Seminars in Diagnostic Pathology 2006: 23(2) 70-83.  Used with the permission of Elsevier.
 Tumor Parameters      Risk of Progressive Disease a
 Mitotic
Index		  Size Stomach  Duodenum  Jejunum
or Ileum		  Rectum
≤ 5 per
50 hpf		  ≤ 2cm  none  none  none  none
 > 2 ≤ 5cm  very low
(1.9%)		  low
(8.3%)		  low
(4.3%)		  low
(8.5%)
 > 5 ≤ 10 cm  low
(3.6%)		  insufficient
data		  moderate
(24%)		  insufficient
data
 > 10 cm  moderate
(10%)		  high
(34%)		  high
(52%)		  high
(57%)
> 5 per
50 hpf		  ≤ 2 cm  none b  insufficient
data		  high b  high
(54%)
 > 2 ≤ 5 cm  moderate
(16%)		  high
(50%)		  high
(73%)		  high
(52%)
 > 5 ≤ 10 cm  high
(55%)		  insufficient
data		  high
(85%)		  insufficient
data
 > 10 cm  high
(86%)		  high
(86%)		  high
(90%)		  high
(71%)
 a defined as metastasis or tumor-related death
b denotes small number of cases
 Data based on longterm followup of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.

 

MSKCC Nomogram to estimate probability of recurrence-free survival

The Memorial Sloan-Kettering Cancer Center sarcoma team developed a nomogram to estimate the probability of recurrence-free survival after surgery for a primary GIST (Gold et al, 2009).  This tool was developed using a group of GIST patients from MSKCC, then validated using two different populations of GIST patients from other institutions.  You can read an explanation of the nomogram by Dr. Ronald DeMatteo in our Ask the Professional section at this link. You can also use a calculator version of the nomogram on the MSKCC website.  The nomogram is also included in the NCCN 2010 report Optimal Management of Patients with GIST — Update of the NCCN Clinical Practice Guidelines.  In contrast to the Miettinen and Lasota risk table that predicts recurrence, the MSKCC nomogram predicts the probability of recurrence-free survival at 2 years and at 5 years.  Therefore, the predicted probability of recurrence is 100% minus the predicted probability of recurrence-free survival.

 

AJCC Staging for GIST (gastrointestinal stromal tumor)

The American Joint Committee on Cancer (AJCC) has introduced new staging criteria for GIST in its new 7th edition manual (Edge et al, 2010).  There has never been AJCC staging for GIST in the past, but this new scheme is to be used from 2010 on (until it is revised). Therefore, pathology reports on new tumors and new biopsies from 2010 onward may use this scheme (at the discretion of the pathologist)

If you have a diagnosis from earlier than 2010, you could see where your tumor would fall in this new scheme, but there is no real new information here — it is just a new system for describing the same information. In a nutshell, they adopted the Miettinen and Lasota (AFIP) risk table shown as Table 3 above, and then they applied the “TNM” system to it.

All the AJCC staging schemes use “TNM” — it stands for Tumor Node Metastasis.

  • Tumor size yields a “T” category.
  • Lymph node status yields an “N” category that is almost always 0 for GIST since GIST rarely spreads to lymph nodes.
  • Metastasis status yields an “M” category of 0 if there is no metastasis, and 1 if metastasis has occurred.

In addition, a “Grade” category is assigned based on mitotic rate: “low grade” if there are 5 or fewer mitoses in 50 high-power fields, and “High Grade” if there are 6 or more mitoses in 50 HPF.

Staging is different for gastric & omental versus other GISTs, indicating a greater risk of recurrence for non-gastric GISTs. You can see the AJCC staging for GIST on our page GIST Prognosis: Risk of Recurrence or Aggressive Behavior written by expert pathologists Alexander Lazar MD PhD and Jason Hornick MD PhD.

You can access the following paper that gives additional details and shows a checklist for pathologists in how to apply this scheme.  Click the paper’s title below for access.  This link is provided with permission from Archives of Pathology & Laboratory Medicine. Copyright 2010. College of American Pathologists.

Protocol for the Examination of Specimens From Patients With Gastrointestinal Stromal Tumor
Brian P. Rubin, MD, PhD, Charles D. Blanke, MD, George D. Demetri, MD, Ronald P. DeMatteo, MD, Christopher D. M. Fletcher, MD, John R. Goldblum, MD, Jerzy Lasota, MD, PhD, Alexander Lazar, MD, PhD, Robert G. Maki, MD, PhD, Markku Miettinen, MD, PhD, Amy Noffsinger, MD, Mary Kay Washington, MD, PhD, Thomas Krausz, MD, and for the Members of the Cancer Committee, College of American Pathologists.
Arch Pathol Lab Med. 2010 Feb;134(2):165-70.  PMID: 20121601

Nomogram for Estimating the Probability of Recurrence-Free Survival after Surgical Resection of Primary GIST

 

Other Risk Factors

Other tumor characteristics often found to be associated with a greater risk of malignancy include:

  • presence of necrosis (which correlates with large tumor size)
  • high cellularity
  • infiltration of adjacent structures
  • serosal 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).

 

 

References

Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, Odén A, Gustavsson B, Kindblom LG, Nilsson B.
Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis.
Gastroenterology. 2006 May;130(6):1573-81. PMID: 16697720

Bearzi I, Mandolesi A, Arduini F, Costagliola A, Ranaldi R.
Gastrointestinal stromal tumor. A study of 158 cases: clinicopathological features and prognostic factors.
Anal Quant Cytol Histol. 2006 Jun;28(3):137-47. PMID: 16786723

Cho S, Kitadai Y, Yoshida S, Tanaka S, Yoshihara M, Yoshida K, Chayama K.
Deletion of the KIT gene is associated with liver metastasis and poor prognosis in patients with gastrointestinal stromal tumor in the stomach.
Int J Oncol. 2006 Jun;28(6):1361-

Edge SE, Byrd DR, Carducci MA, Compton CC, eds.
AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010

Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW.
Diagnosis of gastrointestinal stromal tumors: A consensus approach.
Hum Pathol. 2002 May;33(5):459-65.  PMID: 12094370

Goh BK, Chow PK, Yap WM, Kesavan SM, Song IC, Paul PG, Ooi BS, Chung YF, Wong WK.
Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified Armed Forces Institute of Pathology risk criteria.
Ann Surg Oncol. 2008 Aug;15(8):2153-63. PMID: 18546045

Gold JS, Gönen M, Gutiérrez A, Broto JM, García-del-Muro X, Smyrk TC, Maki RG,Singer S, Brennan MF, Antonescu CR, Donohue JH, DeMatteo RP.
Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. 
Lancet Oncol. 2009 Nov;10(11):1045-52. PubMed PMID: 19793678

Miettinen M, Lasota J.
Gastrointestinal stromal tumors: pathology and prognosis at different sites.
Semin Diagn Pathol. 2006 May;23(2):70-83.  PMID: 17193820

Miettinen M, Lasota J.
 Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.
Arch Pathol Lab Med. 2006 Oct;130(10):1466-78. PMID: 17090188

Miettinen M, Sobin LH, Lasota J.
Gastrointestinal stromal tumors of the stomach: a clinicopathologic,immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up.
Am J Surg Pathol. 2005 Jan;29(1):52-68.  PMID: 15613856

Miettinen M, El-Rifai W, H L Sobin L, Lasota J.
Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review.
Hum Pathol. 2002 May;33(5):478-83. PMID: 12094372

Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, Yamada T, Nawata H, Tsuneyoshi M.
 Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade.
Hum Pathol. 2005 Jul;36(7):828-37. Erratum in: Hum Pathol. 2006 Apr;37(4):503. PMID: 16084954

Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B,Sablinska K, Kindblom LG.
Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden.
Cancer. 2005 Feb 15;103(4):821-9.
PMID: 15648083

Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG.
Gastrointestinal stromal tumors in Iceland, 1990-2003: the Icelandic GIST study, a population-based incidence and pathologic risk stratification study.
Int J Cancer. 2005 Nov 1;117(2):289-93.  PMID: 15900576