Understanding pediatric GIST may provide important clues

Gastrointestinal Stromal Tumors (GIST) in young people is known as pediatric GIST. It is thought to be very rare. But is it as rare as we think? Are the 27 young members of The Life Raft Group a significant portion of the pediatric GIST patients in the world? As we try to answer that question, let's also take a closer look at some of the different types of pediatric GIST.

Like adult GIST, pediatric GIST can be further divided into subgroups. The most familiar and perhaps the most common type does not seem to have a distinct name so let's just call it "Pediatric GIST." It most commonly affects girls between the ages of about 6 to 18 and almost always starts in the stomach. Dr. Carney

The second well-known type of GIST affecting young people is called "Carney's Triad." It is named after Dr. P. Aidan Carney who first described it in 1977. Patients with Carney's triad may have several different types of tumors including GIST, pulmonary chondroma, and/or functioning extra-adrenal paraganglioma. If any two of these tumors are present, a diagnosis of the "triad" can be made, particularly if age and sex factors are supportive. It is important that patients less than 35 years of age who have any one of the three tumors be examined periodically in search of the others according to Dr. Carney. By 1983, 24 cases had been reported and, by 1999, 79 cases had been reported. Carney's triad affects mostly younger females but there is one report of an 84 year old man who was found to have Carney's triad during an autopsy.

In 2002, Dr. Carney and Dr. Constantine Stratakis reported on a new syndrome that was similar to, yet distinct, from Carney's triad. They had found 12 patients in 5 families with two parts of the "triad," paraganglioma and GIST. Since this condition appeared to be inheritable and the "true Carney's triad" did not, Carney and Stratakis concluded that this syndrome was different than Carney's triad and called it "Familial Paraganglioma and Gastric Stromal Sarcoma" (GIST is sometimes called "Gastric Stromal Sarcoma"). The patients varied in age from 9 to 46 years old at diagnosis with 9 of the 14 patients under the age of 23.

When looking at multiple medical reports, it appears like there may be one more type of pediatric GIST. The youngest GIST patients of all may be born with GIST and need surgery soon after birth. This type of GIST, called neonatal or congenital GIST, appears to affect both boys and girls (although girls are more common) and seems to start in the intestines instead of the stomach. We found 6 cases described as GIST in newborns, however there seems to be some doubt about whether or not these are really leiomyosarcomas or GISTs.

A search of the internet found seven scientific papers that report more than one pediatric GIST patient from a single institution. These papers provide important insights into the mysteries of pediatric GIST. The Life Raft Group pediatric GIST database forms an eighth source of this type of data and is the second largest series.

Dr. Sonam Prakash, Dr. Christina Antonescu and others of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York reported on 15 cases of young people with GIST. Of the 350 GIST patients in the MSKCC database there were 5 patients less than 18 years old (1.4% of all of their GIST patients) and 10 patients between 18 and 30 years old. Dr. Antonescu is the principal pediatric GIST researcher for The Life Raft Group research project.

The MSKCC team wanted to look at the differences between the younger patients (below 18) and the older patients (18 to 30 years old). They found that the younger patients tended to fit the "classical" pattern of pediatric GIST. The older group had characteristics of both adult GIST (such as a high rate of KIT mutations) and pediatric GIST. The tumors of patients in the older group tended to express genes in patterns that were similar to the younger pediatric GIST patients rather that the adult GISTs. Two of the patients in the older group had characteristics that strongly resembled those of the younger group, and the MSKCC doctors noted that at least one of these cases may have developed in childhood and not detected until adulthood.

Some of the things the MSKCC team and others have noted to be typical of pediatric GIST include:

• Affects mostly females. Almost always occurs in the stomach, often as multiple nodules.
• Tumors do not usually have the KIT or PDGFRA mutations that occur in the vast majority of adult GISTs.
• Metastases to the lymph nodes appear to be more common than adult GIST.
• The tumor cells tend to be shaped differently. Pediatric GISTs tend to resemble "epithelioid" cells (more rounded and more similar to typical non-sarcoma type cancers), while adult GISTs tend to have a "spindle" shape.

Dr. Victoria Price, Dr. Alberto Pappo and others from the Hospital for Sick Children in Toronto, Canada reported on six young GIST patients. They reviewed hospital records that covered an 11 year span. They had treated five of the patients at their hospital and had acted as a consultant for the pathology of the sixth patient. Four of the patients were girls and two were boys. One of the boys and one of the girls had additional tumor(s) that were typical of "Carney's Triad." Another boy (age 13) did not fit the usual pattern of pediatric GIST because of his gender (male) and the fact that he had a mutation in the c-kit gene (which is more typical of adults with GIST).

Dr. Monica Cypriano, Dr. Najat Daw and others from St. Jude Children's Research Hospital in Memphis, Tennessee reported on seven young GIST patients. This series was somewhat unusual in that only two of the seven patients had tumors that started in the stomach. The patients in this study were diagnosed over a 40 year time span between 1962 and 2002.

There are reports of two cases from Ireland and three cases from Atlanta, Georgia in the United States. All five of these cases started in the stomach.

A 1999 report by Dr. Jody Z. Kerr and others reported four cases of Gastrointestinal autonomic nerve tumors (GANTs). GANTs are tumors that are very similar to GISTs. The authors noted many features that were similar to pediatric GISTS. Given the incomplete understanding of GISTs in 1999, the question that arises is whether these tumors would have been classified as GISTs if they were examined using today's standards.

The largest case series comes from the Armed Forces Institute of Pathology (AFIP). This study looked at 44 cases of pediatric GISTs that were submitted to the AFIP from the United States and Canada between 1970 and 1996. Patients in this study ranged from 5 to 21 years old at the time of diagnosis. Only GISTs with a primary tumor in the stomach were included in this study. These 44 cases represented 2.5 percent of the stomach GISTs submitted to the AFIP in this time frame (44 of 1782 patients).

The AFIP series is particularly striking in its gender distribution according to age. They report 24 females between the age of 6 and 15 and no males. Between the ages of 16 and 21, however, the gender distribution is completely different with 11 males and 8 females. They did report one 5 year old male.

When you combine all of the reports some patterns begin to emerge (subject to the considerable limitations of this review). Patients seem to form several groups according to age and primary tumor location:

• Newborns-primary tumors tend to be located in the intestines.
• 1 to 3 years old- We were unable to find any reports of patients diagnosed between the ages of one to three.
• 4 to 5 years old- Three of four were located in the intestines, only one in the stomach.
• Summary-Newborns to 6 years old-Seems to affect both females and males with a tendency towards intestinal primary (includes small intestine, cecum and colon). Probably needs more expert GIST pathology review to verify that these are true GISTs and not leiomyosarcomas.
• 6 to 15 years old- The vast majority are females and the vast majority have a stomach primary. This group appears to be the largest and probably comes closest to being representative of "Pediatric GIST." It is interesting to note that 8 of the 9 males in this group had primary tumors in the stomach, just like the girls.
• 16 years and up- Although still dominated by females and a primary tumor location in the stomach, we start to see a transition towards adult GIST with both more males and more non-stomach primary tumors.

Some observations and questions

It is interesting to note that there are more cases of Carney's triad reported in the literature than pediatric GIST; but in the eight reported series of patients (including The Life Raft Group series) Carney's triad seemed to be a distinct minority. This raises the question of the ratio of pediatric GIST to Carney's triad. Are there a lot more pediatric GIST patients than the 79 reported Carney's triad patients?

Questions

1. Are the newborn GISTs really GISTs?
2. Is the intestinal location of GISTs in patients below six years old an important clue or a red herring?

Limitations

There are some differences between these series of patients. The AFIP series looked only at GISTs with a stomach primary. The pathology expertise almost certainly varies considerably; some of these cases may have incorrectly been classified as GIST. Some series used different age cutoff points (29 for The Life Raft Group, 21 for the AFIP and 18 and 30 for the MSKCC series).

There are also some limitations to this newsletter article on pediatric GIST. It is based on a cursory review of the literature. Many articles were only reviewed in abstract form. It is very possible that some patients have been counted more than once (such as in a series and in an individual article).

Conclusion

Six years ago GIST was very poorly understood. The basic research that found a molecular target (KIT) and an excellent targeted drug (Gleevec) has sparked tremendous advances in the understanding of GIST. Today adult GIST can be divided into many different groups. Although in its beginning stages, therapy is beginning to be optimized for these different groups. The Life Raft Group research team includes many of the top GIST researchers in the world. This group has led the way, doing research that has revolutionized the treatment of GIST and they are working to understand and develop more effective therapies for pediatric GIST. Understanding pediatric GIST may provide important clues to help them understand adult GIST as well.