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 recently beginning to be well understood. Given the critical job of the pathologist, newly diagnosed GIST patients may sometimes 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 can be difficult. Experience is important here. A team of doctors and pathologists who are all experienced with GIST will often be better able to develop and implement a specific treatment plan based on each patients unique situation.

Diagnosis of Cell Type

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 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

KIT positive-about 95% of the time (the term c-Kit or CD117 may be used instead of KIT).
DOG-1 positive - about 98% of the time9
CD34 positive-60% to 70% of the time.
SMA postive-30% to 40% of the time.
Desmin positive-very rare
S-100 positive-5%+
PKC theta (PKCθ) is expressed in almost all GIST but that may not be commercially available.
Increasingly, a negative stain for SDHB is helping to identify pediatric-type GIST.

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:

Primary tumor size (taken in the longest dimension)
Primary tumor location
Mitotic activity of primary tumor
- May be called mitotic rate or mitotic count
- A measure of how fast the tumor is growing
- Must be taken from most mitotically active portion of tumor
- Mitotic rate cannot be calculated from tissue that is removed after taking neoadjuvant Gleevec
- Needle biopsies may underestimate the mitotic rate as they may miss the most mitotically active part of the tumor. However, if the rate is high (for example above 5/50 HPF), then it may still be used to calculate risk using some methods.

Other important factors for a high risk of recurrence include:

Rupture of the tumor either prior to or during surgery. Tumor rupture is included as a risk factor in the Joenssu Pooled Analysis (contour maps) and the Modified NIH criteria.
Failure to obtain clear margins during surgery, although a R1 resection may not be as high risk as tumor rupture. ESMO guidelines (Europe) address re-excision for R1 margins.
Genotype - Deletions in KIT exon 11, especially deletions of codons 557 and 558 have been shown to increase the chances of a recurrence2,8. Genotype has not yet been integrated into any of the currently used risk methods.

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.

Note:

for GIST patients not taking Gleevec.

Preventative Gleevec for GIST

Joenssu - Pooled analysis

Using contour maps, provides a visual aid in understanding risk

This method of estimating risk of recurrence is based on a pooled analysis of 10 population-based series of patients with operable GIST that did not receive adjuvant imatinib after surgery. Over 2500 GIST patients were included in this analysis. Importantly, tumor rupture was added as a separate category. Most other systems only note tumor rupture as higher risk, this system integrates tumor rupture into the risk assessment.

Effect of tumor size, mitotic rate, location and rupture on risk of recurrence (graph format)

This paper was published in The Lancet Oncology on December 7th, 2011 (early online edition)10.

Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts

View full size contour map

GIST Nomogram

An easy to use tool is 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 localized 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.

The Memorial Sloan-Kettering Cancer Center nomogram can be accessed through this webpage:
GIST Nomogram.

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.

Modified NIH Method
Adds tumor rupture and site to the NIH system

The modified NIH method adds several addition criteria to the original GIST Workshop (NIH) method (described below)12. This method was proposed by Heikki Joenssu, MD, PhD, in 2008. In addition to tumor size and mitotic rate (original NIH criteria), it adds tumor location and tumor rupture. Most of the major methods do not include tumor rupture as a risk factor. High risk tumors as defined by this method have more than a 15% to 20% risk of a recurrence.

NOTE: Many patients classified as intermediate risk using other methods can be reclassified as either high or low risk when using the modified NIH method. Commentary by Dr. Joensuu; Adjuvant Therapy for High-Risk GIST: Considerations for Optimal Management (September, 2012)

Modified NIH Method
	Size	Mitotic Count	Primary Tumor Site
Very low risk	<2.0 cm	≤5/50 HPF	Any
Low risk	2.1-5.0 cm	≤5/50 HPF	Any
Intermediate risk	2.1-5.0 cm	>5/50 HPF	Gastric
	<5.0 cm	6-10 HPF	Any
	5.1-10 cm	≤5 HPF	Gastric
High risk	Any	Any	Tumor rupture
	>10 cm	Any	Any
	Any	>10 HPF	Any
	>5.0	>5 HPF	Any
	2.1-5.0 cm	>5 HPF	Nongastric
	5.1-10.0 cm	≤5/50 HPF	Nongastric
Abbreviation: HPF = high-power field.

AFIP-Miettinen Method
A commonly used system

In April, 2010, the Journal of the National Comprehensive Cancer Network issued a "NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors".4 These guidelines contain both the AFIP-Miettinen method of determining risk (defined as metastasis or tumor-related death) and the GIST nomogram system. 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 Miettinen et al.5,6

Risk Stratification of Primary GIST by Mitotic Index, Size, and Site*
Tumor Parameters		*Risk of Progressive Disease (%)**
Group	Size	Mitotic rate	Gastric	Jejunal/Ileum	Duodenal	Rectum
1	≤ 2 cm**	≤ 5 per 50 hpf	None (0%)	None (0%)	None (0%)	None (0%)
2	>2 ≤ 5 cm		Very low (1.9%)	Low (4.3%)	Low (8.3%)	Low (8.5%)
3a	> 5 ≤ 10 cm		Low (3.6%)	Moderate (24%)	High (34%) ǂ	High† (57%) ǂ
3b	> 10 cm		Moderate (12%)	High (52%)	High (34%) ǂ	High† (57%) ǂ

4	≤ 2 cm	> 5 per 50 hpf	None†	High† (50%)	§	High (54%)
5	> 2 cm ≤ 5 cm		Moderate (16%)	High (73%)	High (50%)	High (52%)
6a	> 5 cm ≤ 10 cm		High (55%)	High (85%)	High (86%) ǂ	High (71%) ǂ
6b	> 10 cm		High (86%)	High (90%)	High (86%) ǂ	High (71%) ǂ

Abbreviations: GIST, gastrointestinal stromal tumor; hpf, high power field.
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.
ǂ Groups 3a and 3b or 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.

**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".7

Image courtesy of Wikipedia; see Wikipedia articles for general information about:

Duodenum

Jejunum

Ileum

GIST Workshop method (NIH)
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:

Rupture of the tumor either prior to or during surgery.
Failure to obtain clear margins during surgery.

Future Directions

Gleevec is an outstanding drug and a lifeline for the majority of GIST patients. However, it does have side-effects and these can be significant for some patients. In addition, like all cancer treatments, it is expensive. Thus it is extremely desirable to find better methods to determine which patients need to take Gleevec and which patients are essentially “cured” by surgery and don’t need to take Gleevec. In the February, 2012 issue of the LRG newsletter, LRG Research Team member, Dr. Maria Debiec-Rychter describes three new genomic-based methods that appear to significantly outperform current methods of risk assessment11:

• CINSARC

• AURKA expression

• Genomic Index

One of these methods, the CINSARC method, appears to have broader applicability to the wider sarcoma community as well. Importantly, the DNA CGHarray technique performed by Dr. Debiec-Rychter and colleagues can be performed from paraffin-embedded tumor tissue, the type of tissue that is already available/existing for most GIST patients.

View the LRG story

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. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience.

Wozniak A, Rutkowski P, Piskorz A, Ciwoniuk M, Osuch C, Bylina E, Sygut J, Chosia M, Rys J, Urbanczyk K, Kruszewski W, Sowa P, Siedlecki J, Debiec-Rychter M, Limon J; on behalf of Polish Clinical GIST Registry. Source Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.

3. 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.

4. NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors
George D. Demetri, MD, Margaret von Mehren, MD, Cristina R. Antonescu, MD, Ronald P. DeMatteo, MD, Kristen N. Ganjoo, MD, Robert G. Maki, MD, PhD, Peter W.T. Pisters, MD, Chandrajit P. Raut, MD, MSc, Richard F. Riedel, MD, Scott Schuetze, MD, PhD, Hema M. Sundar, PhD, Jonathan C. Trent, MD, PhD and Jeffrey D. Wayne, MD

5. 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

6. Gastrointestinal stromal tumors: pathology and prognosis at different sites.
Miettine, M., Lasota J.

7. 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.

8. ASCO 2010-Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results of the intergroup phase III trial ACOSOG Z9001.
C. L. Corless, K. V. Ballman, C. Antonescu, C. D. Blanke, M. E. Blackstein, G. D. Demetri, M. von Mehren, R. G. Maki, P. W. Pisters, R. P. DeMatteo, American College of Surgeons Oncology Group; Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR; Mayo Clinic Rochester, Rochester, MN; Memorial Sloan-Kettering Cancer Center, New York, NY; University of British Columbia/British Columbia Cancer Agency, Vancouver, BC, Canada; Mount Sinai Hospital, Toronto, ON, Canada; Ludwig Center, Dana-Farber Cancer Institute/Harvard Cancer Center and Sarcoma Center, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; University of Texas M. D. Anderson Cancer Center, Houston, TX

9. The Novel Marker, DOG1, Is Expressed Ubiquitously in Gastrointestinal Stromal Tumors Irrespective of KIT or PDGFRA Mutation Status
West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, van de Rijn M:

10. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts
Prof Heikki Joensuu MD,Aki Vehtari DSci,Jaakko Riihimäki MSc,Toshirou Nishida MD,Sonja E Steigen MD,Peter Brabec MSci,Prof Lukas Plank MD,Bengt Nilsson MD,Claudia Cirilli BSc,Chiara Braconi MD,Andrea Bordoni MD,Magnus K Magnusson MD,Zdenek Linke MD,Jozef Sufliarsky MD,Massimo Federico MD,Jon G Jonasson MD,Angelo Paolo Dei Tos MD,Piotr Rutkowski MD

11. Mitotic Checkpoints and Chromosome Instability are Strong Predictors of Clinical Outcome in Gastrointestinal Stromal Tumors
Pauline Lagarde, Gaëlle Pérot, Audrey Kauffmann, Céline Brulard, Valérie Dapremont, Isabelle Hostein, Agnès Neuville, Agnieszka Wozniak, Raf Sciot, Patrick Schöffski, Alain Aurias, Jean-Michel Coindre, Maria Debiec-Rychter, Frédéric Chibon.

12. Risk stratification of patients diagnosed with gastrointestinal stromal tumor
Heikki Joensuu MD, PhD