Science and Biology of Pediatric GIST

/Science and Biology of Pediatric GIST
Science and Biology of Pediatric GIST 2018-06-20T12:21:10+00:00

Although the exact incidence is still somewhat unclear, it is now estimated that between 3,00 and 5,000 people in the United States develop GIST. GISTs occurring in younger patients (under 18) are much rarer, accounting for less than 2% of all GIST patients. 1,2 In the past, age has defined Pediatric GIST. With increased understanding over the years, we now recognize that this form of GIST can be diagnosed after the age of 18 as well. Pediatric-like GIST is also known as SDH-deficient GIST. The common thread that links all the subtypes of Pediatric GIST seems to be that they all have some type of defect in the succinate dehydrogenase (SDH) protein. See Wildtype GIST & SDH: What to know by Jennifer Wright.

The table below describes the differences typically seen between adult GIST and pediatric-like GIST.

Typical differences between adult and pediatric GIST
Characteristic
Adult GIST
Pediatric-like GIST
Gender distribution about 48% female up to 85% female
Site of primary Anywhere in the GI tract Usually starts in the stomach
Presentation Single primary site may present as mutifocal (multiple tumors in the stomach)
Metastasis to lymph nodes Rare More common
Growth More aggressive Less aggressive
Typical histology spindle-shaped epithelioid
Response to imatinib Has a high response rate Undefined; but generally believed to be lower
Mutations KIT (75%)
PDGFRA (8%)
BRAF (rare)
85% wildtype; SDH mutations, SDHB inactivation, IGF-1R overexpression

Diagnosis and Monitoring

The most common symptoms of pediatric GIST are:

  • Anemia and other symptoms related to bleeding (such as blood in the stool). In one series of 6 patients, all presented with iron-deficient anemia3
  • Abdominal pain or abdominal mass4

As in adult GIST, prior to about 2000, pediatric-like GIST patients may have previously been diagnosed with leiomyosarcoma, leiomyoma, leiomyoblastoma, or GANT. As understanding of the biology of GIST increased, it was recognized that many tumors in these other categories were actually GISTs.

Risk Assessment

Pediatric GISTs behave differently than adult GISTs. Pediatric GIST may present with one or multiple tumors in the stomach (multi-focal). A tumor that is removed surgically may recur, either near the original site (a local recurrence) or at a distant site such as the liver. Local recurrences in the stomach may be a single tumor or multiple stomach tumors. When a tumor recurs at a distant site it is called a metastasis.

The risk of recurrence in adults with GIST has been fairly well defined. Two factors, size of the primary tumor and rate of growth, (measured by the mitotic rate) are the primary factors that affect the risk of recurrence in adults. In pediatric GIST however, work done at the U.S. Armed Forces Institute of Pathology (AFIP), suggests that these factors probably do not accurately predict the risk of recurrence in pediatric GIST. The table below is probably one of the most complete risk comparisions between adult GIST and pediatric GIST.

Prognosis of 30 GISTs in Children and Young Adults by Prognostic Groups in Comparison with 1055 Gastric GIST patients

(%) of Patients With Metastases in the Group

  Prognostic Group and Definition
Children and Young Adults
All Gastric GIST Patients
  2 (≤5 cm, ≤5/50 HPF)
1/6 (17%)
6/320 (2%)
  3A (5 ≤10 cm, ≤5/50 HPF)
2/7 (28%)
8/229 (3%)
  3B (> 10 cm, ≤5/50 HPF)
1/2 (50%)
17/140 (12%)
  5 (>2 ≤5 cm, >5/50 HPF)
1/7 (14%)
16/99 (16%)
  6A (>5 ≤10 cm, >5/50 HPF)
3/5 (60%)
52/96 (54%)
  6B (>10 cm, >5/50 HPF)
2/3 (67%)
89/108 (82%)

Note: Only cases with follow-up and defined tumor size are included.

Gastrointestinal Stromal Tumors of the Stomach in Children and Young Adults
Markku Miettinen, MD,* Jerzy Lasota, MD,* and Leslie H. Sobin, MD†

Treatment

It is important to find doctors experienced in GIST. This experience comes in two basic types: experts in pediatric cancers and experts in adult GIST cancer. Both have unique perspectives and experiences. The best approach might be when doctors from both fields collaborate with each other.

Surgical removal of the tumor(s) has historically been the primary treatment for pediatric GIST. The types of operations have historically varied from a simple local excision to a total gastrectomy. In some cases, surgery provides long-term relief. In other cases, tumors return, either locally (near the original site, such as another stomach tumor(s), or distant from the original site (metastases).

Recently, dramatic success has occurred in the treatment of adults with metastatic or inoperable GISTs (in cases where surgery is not possible). The genetic defects that cause adult GIST (KIT and PDGFRA mutations) can now be targeted with a drug called Gleevec (also known as imatinib and Glivec). While this drug (and a second generation inhibitor, Sutent) is very effective in adult GIST, the vast majority of pediatric GISTs do not have the same types of mutations. Response data is limited, but the early ancedotal indications are that Gleevec is not as effective in pediatric GIST as it is in adult GIST.

Consolidating Resources

Because Pediatric GIST is so rare, it is difficult for doctors to develop expertise because few doctors see more than one or two pediatric GIST patients. Doing research on pediatric GIST is also difficult because it is hard for one institution to accumulate enough tissue. Whenever possible, it is recommended to see a doctor with as much pediatric GIST experience as possible.

In cooperation with several leading pediatric and GIST centers, the Life Raft Group is establishing both physical centers of excellence and a virtual center of excellence. In the United States, two institutions are initially participating as physical centers of excellence. Doctors from these same teams and other doctors as needed will also participate in a virtual center of excellence. Patients not able to travel to the physical centers can have their records reviewed by a multidisciplinary team of pediatric GIST experts. These experts will review the case and then meet by teleconference (or video conference) and discuss the case. For further information on how to have a case reviewed by the virtual center, contact the Life Raft Group at 973-837-9092 or at liferaft@liferaftgroup.org.

Memorial Sloan-Kettering Cancer Center
New York, NY
Michael LaQauglia, M.D. Pediatric Surgeon
Cristina Antonescu, M.D., Pathologist and Head of the Pediatric GIST research project as well as the pediatric GIST tumor bank.

Texas Children’s Hospital
Houston, TX
Alberto Pappo, M.D. Pediatric Oncologist
Jed Nuchtern, M.D. Pediatric Surgeon

Next Steps:

Wildtype GIST

Information on Mutations in GIST and Mutational Testing

Newly Diagnosed Patients

Join the Life Raft Group and the GIST Collaborative Tissue Bank

Contribute to Real World Evidence working toward a cure!

References

  1. Gastrointestinal Stromal Tumors in Children and Young Adults. A Clinicopathologic, Molecular, and Genomic Study of 15 Cases and Review of the Literature. J Pediatr Hematol Oncol  Volume 27, Number 4, April 2005. Sonam Prakash, MD, Lisa Sarran, MS, Nicholas Socci, PhD, Ronald P. DeMatteo, MD, Jonathan Eisenstat, MD, Alba M. Greco, MD, Robert G. Maki, MD, PhD, Leonard H. Wexler, MD,k Michael P. LaQuaglia, MD, Peter Besmer, PhD, and Cristina R. Antonescu, MD
  1. Gastrointestinal Stromal Tumors of the Stomach in Children and Young Adults A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 44 Cases With Long-Term Follow-Up and Review of the Literature. Am J Surg Pathol  Volume 29, Number 10, October 2005 Markku Miettinen, MD,* Jerzy Lasota, MD,* and Leslie H. Sobin, MD
  1. Clinical and Molecular Characteristics of Pediatric Gastrointestinal Stromal Turmos (GISTs) Victoria E. Price, Maria Zielenska, Susan Chilton-MacNeill, Charles R. Smith and Alberto S. Pappo Pediatr Blood Cancer
  1. Pediatric Gastrointestinal Stromal Tumors and Leiomyosarcoma The St. Jude Children’s Research Hospital Experience and a Review of the Lieterature CANCER July 1, 2004 / Volume 101 / Number 1
  1. Sunitinib treatment of pediatric metastatic GIST after failure of imatinib. K. A. Janeway, D. C. Matthews, J. E. Butrynski, G. Z. D’Amato, S. Agresta, C. Garrett, C. L. Corless, K. H. Albritton, G. D. Demetri Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 9519

Core Values

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