Diagnosis and Risk Assessment
Identifying the type of cell from which a cancer has developed is a specialized art. The doctors who make these judgments are pathologists, and their job is absolutely critical! If the oncologist does not know what the type of cancer is, he or she does not know how to treat it. The pathology and diagnosis of GIST are only recently beginning to be understood, as we discuss below. Given the critical job of the pathologist, newly diagnosed GIST patients should consider a second opinion of their pathology reports (unless the pathology was initially done by a pathologist who was very experienced with GIST). While many pathologists may be able to accurately diagnose GIST now, predicting the behavior of GIST is very difficult. Experience is critical here. A team of doctors and pathologists who are all very experienced with GIST will usually be better able to develop and implement a specific treatment plan based on each patients unique situation.
Gastrointestinal Stromal Tumor (GIST) Workshop
The Novartis International website
A biopsy is usually used to aid in the diagnosis of cancer and GIST. Tissue samples are prepared from the biopsy sample. One method that the pathologist uses to classify tissues is called immunohistochemistry. Using this technique, the pathologist applies various "antibodies" to the tissues. These antibodies are each designed to react with specific features (proteins) on the cell surface. The most important antibody that is applied when GIST is suspected is the KIT antibody. When these antibodies bind to their specific target on the cell surface they produce a "stain" or change in color of the sample. So when the KIT antibody is applied, if the cell surface has the KIT protein present on the surface, the sample will "stain positive". This is what is known as "KIT positive" and means that this cell has KIT receptors on its surface.
With very rare exceptions1, GIST tumors will stain positive for KIT. This means that the cell is manufacturing or using the KIT protein. In the case of KIT, this protein is a receptor. (See KIT Receptor Image)
Using immunohistochemical staining, GIST cells can be summarized as follows:1
Two other stains (tests) that are expressed in almost all GIST but that may not be commercially available include:
- DOG-1
- PKC theta (PKCθ)
Prognostic Factors and Risk Assessment
CAUTION: Pediatric-type GIST may have a very different potential for metastases and these tables should not be used for estimating risk for pediatric-type GIST.
Many attempts have been made to classify GISTs as to their potential for malignant behavior. Pathologists who are GIST experts, currently think it most prudent to classify GISTs based on risk assessment, rather than try to classify them as benign or malignant. At least some GIST experts think it is unwise to use the term "benign" with GIST and that almost all GISTs should be considered as having some malignant potential.
Although many factors have been suggested to contribute to malignant potential, the three most commonly quoted factors are size, primary tumor location and mitotic activity.
Other important factors for a high risk of recurrence include:
- Rupture of the tumor either prior to or during surgery.
- Failure to obtain clear margins during surgery.
- Rupture of the tumor either prior to or during surgery.
- Failure to obtain clear margins during surgery.
Knowing your risk of having a recurrence is one of the most important factors in deciding whether or not you would be a good candidate for taking adjuvant (preventative) Gleevec. See Preventative Gleevec for GIST.
GIST Nomogram An easy to use tool is now available to calculate recurrence-free survival In November of 2009, a paper was published in The Lancet Oncology Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis.5 This nonogram, developed from 127 GIST patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC), can be used to predict the recurrence-free survival of GIST after surgery without receiving adjuvant Gleevec. |
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The Memorial Sloan-Kettering Cancer Center nomogram can be accessed through this webpage: CAUTION: The MSKCC tool predicts recurrence-free survival (RFS). All of the other tools on this page predict the risk of a recurrence. It is easy to confuse the two. In addition, it's easy to confuse recurrence-free survival with survival. Recurrence-free survival has nothing to do with how long you are going to live, it's the predicted chance of your tumor coming back if you do not take Gleevec. The nomogram estimates both the 2 year recurrence-free survival rate and the 5 year recurrence-free survival rate. |
A nonogram is similar to a slide-rule, however, MSKCC has also developed an easier to use webpage where a patient enters in the primary tumor location, tumor size and checks a box if the mitotic rate is equal to or above 5 per 50 HPF. The prediction tool will then calculate the chances of remaining recurrence-free for 2 years and 5 years. |
AFIP-Miettinen System
A commonly used system
In July, 2007, the Journal of the National Comprehensive Cancer Network issued a "NCCN Task force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)-Update of the NCCN Clinical Practice Guidelines".2 These guidelines contain the AFIP-Meittinen method of determining risk (defined as metastasis or tumor-related death). See the table below. The complete guidelines are available on the NCCN website. These guidelines are based on data developed at the Armed Forces Institute of Pathology (AFIP) by Meittinen et al.3,4
| Risk Stratification of Primary GIST by Mitotic Index, Size, and Site* | |||||
|---|---|---|---|---|---|
Tumor Parameters |
Risk of Progressive Disease* (%) |
||||
Mitotic Index |
Size |
Gastric |
Duodenum |
Jejunum/ |
Rectum |
≤ 5 per 50 hpf |
≤ 2 cm** | None (0%) | None (0%) | None (0%) | None (0%) |
| >2 ≤ 5 cm | Very low (1.9%) | Low (4.3%) | Low (8.3%) | Low (8.5%) | |
| > 5 ≤ 10 cm | Low (3.6%) | Moderate (24%) | (Insuff. data) | (Insuff. data) | |
| > 10 cm | Moderate (10%) | High (52%) | High (34%) | High (57%) | |
| > 5 per 50 hpf | ≤ 2 cm | None† | High† | (Insuff. data) | High (54%) |
| > 2 cm ≤ 5 cm | Moderate (16%) | High (73%) | High (50%) | High (52%) | |
| > 5 cm ≤ 10 cm | High (55%) | High (85%) | (Insuff. data) | (Insuff. data) | |
| > 10 cm | High (86%) | High (90%) | High (86%) | High (71%) | |
Abbreviations: GIST, gastrointestinal stromal tumor; hpf, high power field; Insuff, insufficient.
Adapted from Miettinen and Lasota, 2006. Data are based on long-term follow-up of 1055 gastric, 629 small intestinal,
144 duodenal, and 111 rectal GISTs. (Miettinen et al. 2001, 2005, and 2006).
*Defined as metastasis or tumor-related death.
†Denotes small numbers of cases.**NOTE: "Only tumors <2 cm with mitotic rate <5 per 50 HPFs seem to remain consistently free of metastases in follow-up studies; all other categories involve metastatic risk (See table above). Small, ≤2 cm, mitotically active (>5 per 50 HPFs) GISTs in the rectum have >50% of metastatic rate6. Such very small yet mitotically active GISTs most commonly occur in the rectum, where they can be found as palpable masses, whereas such tumors are extremely rare in the stomach and small intestine".4
Image courtesy of Wikipedia; see Wikipedia articles for general information about:
GIST Workshop method
Especially useful when the primary tumor site is unknown
The following table is older (2002) and was developed from the Gastrointestinal Stromal Tumor (GIST) Workshop. It may still be particularly useful in cases of where the primary site is different than those listed in the table 1 or the primary site is unknown.
Proposed Approach for Defining Risk of Aggressive Behavior in GISTS1 |
||
|---|---|---|
| Size* | Mitotic Count+ | |
| Very low risk | <2cm | <5/50 HPF |
| Low risk | 2-5cm | <5/50 HPF |
| Intermediate risk | >5cm | 6-10/50 HPF |
| 5-10cm | <5/50 HPF | |
| High risk | >5cm | >5/50 HPF |
| >10cm | Any mitotic rate | |
| Any size | >10/50 HPF | |
| Abbreviation: HPF < high-power field. | ||
*Size represents the single largest dimension. Admittedly this may vary somewhat between prefixation and postfixation and between observers. There is a general but poorly defined sense that perhaps the size threshold for aggressive behavior should be 1 to 2 cm less in the small bowel than elsewhere.
+Ideally, mitotic count should be standardized according to surface area examined (based on size of high-powered fields), but there are no agreed-on definitions in this regard. Despite inevitable subjectivity in recognition of mitoses and variability in the area of high power fields, such mitotic counts still prove useful.
Note: The authors of this paper (Diagnosis of Gastrointestinal Stromal Tumors) also conclude that the risk categories as they define them in their paper "...should prove clinically useful, and in light of the uncertainties expressed herein and the well-recognized tendency of these troublesome tumors to pursue an indolent clinical course with a significant risk of late relapse, we also strongly advocate that all patients with GIST be carefully and regularly followed up for an indefinite period."
Other important factors for a high risk of recurrence include:
References
1. Diagnosis of Gastrointestinal Stromal Tumors: A Consensus Approach-Christopher D. M. Fletcher, MD, FRCPATH, Jules J. Berman, MD, PhD, Christopher Corless, MD, PhD, Fred Gorstein, MD, Jerzy Lasota, MD, PhD, B. Jack Longley, MD, Markku Miettinen, MD, Timothy J. O'Leary, MD, PhD, Helen Remotti, MD, Brian P. Rubin, MD, Phd, Barry Shmookler, MD, Leslie H. Sobin, MD, and Sharon W. Weiss, MD
2. NCCN Task Force Report: Optimal
Management of Patients with
Gastrointestinal Stromal Tumor
(GIST)—Update of the NCCN
Clinical Practice Guidelines
George D. Demetri, MD; Robert S. Benjamin, MD;
Charles D. Blanke, MD; Jean-Yves Blay, MD, PhD;
Paolo Casali, MD; Haesun Choi, MD; Christopher L. Corless, MD, PhD;
Maria Debiec-Rychter, MD, PhD; Ronald P. DeMatteo, MD;
David S. Ettinger, MD; George A. Fisher, MD, PhD;
Christopher D.M. Fletcher, MD, FRCPath; Alessandro Gronchi, MD;
Peter Hohenberger, MD, PhD; Miranda Hughes, PhD;
Heikki Joensuu, MD; Ian Judson, MD, FRCP; Axel Le Cesne, MD;
Robert G. Maki, MD, PhD; Michael Morse, MD; Alberto S. Pappo, MD;
Peter W.T. Pisters, MD; Chandrajit P. Raut, MD, MSc;
Peter Reichardt, MD, PhD; Douglas S. Tyler, MD;
Annick D. Van den Abbeele, MD; Margaret von Mehren, MD;
Jeffrey D. Wayne, MD; and John Zalcberg, MBBS, PhD
3. Gastrointestinal Stromal Tumors of the Stomach. A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up. American Journal of Surgical Pathology. 29(1):52-68, January 2005.
Miettinen, Markku MD; Sobin, Leslie H MD +; Lasota, Jerzy MD
4. Gastrointestinal stromal tumors: pathology and prognosis at different sites.
Miettine, M., Lasota J.
5. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. 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.
6. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases.
Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J.
