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News from the 7th NIH Clinic (June 2011)

by Becky Bensenhaver

I was recently fortunate to be able to attend the pre-clinic meeting of the 7th Pediatric and Wildtype GIST Clinic at NIH as a representative of GSI.  As always, Dr. Su Young Kim did an excellent job pulling it all together.  The scientists and researchers of the Consortium (pictured below) are a remarkable group of people.  What follows is a summary of topics discussed.

From all the clinics to date, 80 patients total have been seen at the Clinic. 8 have had Carney Triad, 3 had Carney-Stratakis Dyad, 8 had germline SDH mutations, and 2 had BRAF mutations.  Of the group, only 8 had small bowel primaries; the remainder were gastric.  The current average age of all previous clinic participants is 35.1 years (range 10 to 67 years).The 5-year Overall Survival (OS) rate is 91%, and 5-year Event-Free Survival (EFS) is 28% for 43 patients who were evaluable since initial surgery. This means that at 5-years following first surgery, the chance of still being alive were very good, but the chance for recurrence is high.  There were no significant differences in survival if the patients’ data are stratified by mitotic rate, tumor size, or tumor location: (i.e. the prognostic criteria for “normal” GIST do not apply).  Overall survival does seem to be affected by age, with Adult wildtype (WT) patients (age 40 and older) faring the worst, Pediatric WT patients (age 0-18) better, and Young Adult WT patients (age 19-39) best.

The following figure illustrates the numbers of wildtype GIST patients with different characteristics would be expected out of 4000 GIST patients.

Data analysis of whether adult WT patients are more similar to pediatric patients or to adult mutant patients revealed some interesting differences.  WT adults are 79% female (vs. 46% in KIT mutant GIST). 43% of adult WT GIST patients had epithelioid cell morphology (compared to 20% in KIT mutant GIST patients, and 78% for Pediatric WT patients).  The younger adult WT patients do better than "regular mutant" GIST patients, but there is no difference for older WT pts. SDH immunohistochemistry is 72% negative in clinic patients.  All syndromic (triad & dyad) patients are SDH negative.  Event-free survival did not differ by SDH+ or SDH- status.

Discussion of the criteria for definition of Pediatric GIST is ongoing.  Dr. Kim submitted the following suggestions:

• SDHB negative  (SDH-) by immunohistochemical staining
• Wildtype (WT) for KIT/PDGFRA/BRAF (no mutations)
• Usually female
• stomach primary
• epithelioid cell shape, and
• multifocal presentation  at primary. 

It was also suggested that the definition should be expanded to include anyone who has a concurrent pheochromocytoma or paraganglioma (PHEO/PGL) or pulmonary chondroma.  There was much discussion on this topic.  The term “Pediatric GIST” is not always descriptive of older patients or children with KIT-mutated GIST, or those with NF-1 GIST.  Those who meet the above criteria will be included in a “pediatric-like or wildtype GIST” group.  “Pediatric-like” GIST may, in some ways, be a better descriptor than WT for both pediatric patients and those whose clinical course is similar to that of children with GIST.

Pathologist Dr. Markuu Miettinen at NIH has analyzed data on 66 SDH-deficient GISTS.  All had stomach primaries.  The opinion was expressed by one of the pathologists present that these tumors were more than likely multifocal at diagnosis, even if small or microscopic.  Multifocal sites were frequently intragastric or omental, possibly occurring based on lymphovascular invasion.  This may be a different mechanism of spread for SDH(-) patients compared to KIT-mutant patients, who commonly have blood-borne metastasis to the liver.

NIH will commence with genetic sequencing analyses of SDH(-) clinic participant samples in about 2 weeks.  This testing will provide more information pertaining to functioning of the Krebs cycle (part of mitochondrial cellular respiration) in these patients.  Data from these analyses are expected to be available in about 2 months.   

To date, 8 cases of SDH germline mutations have been identified in Clinic participants.  Interestingly, the male/female incidence is 50/50%, even though the majority of Clinic patients are overwhelmingly female. 

In about another 2 months the NIH will have another round of SDH germline testing results in.

In regard to the insulin-like growth factor receptor 1 (IGF-1R):  IGF-1R can be overexpressed in either SDH(-) or SDH(+) patients, but there is generally a higher expression level associated with SDH(-) status.  An attempt to get an IGF-1R tyrosine kinase inhibitor into a clinical trial has been applied for through the Sarcoma Alliance for Research through Collaboration (SARC) and is still pending.


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