Types of GIST
The "pre-Gleevec" era
Prior to 1998, most of the medical community did not recognize the term GIST. What we now think of as GIST was thought to be a sarcoma of the smooth muscles known as leiomyosarcoma (LMS). In 1998, a Japanese researcher, Seiichi Hirota, discovered mutations in GIST tumors in 5 of 6 GIST patients. He also noted that 94% of the tumors that he believed to be GISTs expressed a protein called KIT and this expression was easily detected with stains that could be applied to the tumor slices (immunohistochemistry).
With Hirota's discovery, a few specialty centers began to recognize that GIST and LMS were different. Treatment however, remained the same until late in 2000 when it became apparent (in early clinical trials) that therapy aimed at blocking the KIT mutations with a new drug called Gleevec was very effective. In stark contrast to the approximately 5% response rate of GIST to traditional chemotherapy, about 85% of GIST patients responded (with at least stability) to Gleevec. It suddenly became very important to distinguish GIST from LMS because the treatments were vastly different.
Just as GIST was broken out from the LMS category in 1998-2000, it has been further subdivided in the 7 years since 2000.
GIST can now be broken down in many different categories: adult GIST, familial GIST, pediatric GIST and GISTs associated with NF1 (neurofibromatosis).
Some of these categories can be broken down further or in different ways, such as by gene mutation (c-kit, PDGFRA or wild-type for both), mutation location within the gene (exon mutation or “genotyping”), and by location of primary tumor (which may cause differences in signaling).
Compared to ten years ago, we have an explosion of new information about GIST.
GIST (Adult GIST)
GIST occurs mainly in adults and like most cancers is more common in older adults. This category is, by far, the most common type of GIST. It can be broken down into different categories that relate to characteristics that affect things such as:
- Chance of recurrence (see the Diagnosis section)
- Response to therapy (see the Gleevec and Sutent sections)
- The type (KIT, PDGFRA or "wild-type") and location (exon 9, exon 11, etc) of gene mutation is one of the most interesting and potentially useful ways that GISTs are subclassified. See Expert Opinions: KIT & PDGFRA mutations in GIST: A to Z by Michael Heinrich, M.D. and Looking for kinase mutations in GISTs: how, when and why? by Christopher Corless, M.D., PhD.
Wild-type GIST (Adult)
Wild-type GIST is a diagnosis of exclusion. If no mutations are found in the KIT gene or the PDGFRA gene, the patient is said to have "wild-type GIST". In 2008, Andrew Godwin, Ph.D., of Fox Chase Cancer Center presented new evidence that wild-type GISTs produce way too much of a protein called IGF1R. Assays to test for IGF1R overexpression are being developed at Fox Chase and clinical trials with an IGF1R inhibitor are in the planning stages3.
For more information see:
New target found for wild-type and pediatric GIST
Medpage Today story and interview with Andrew Godwin: ASCO: Missing mutations hold clue to imatinib (Gleevec) GIST resistance
| Differences between adult and pediatric GIST | ||
|---|---|---|
| Characteristic | Adult GIST |
Pediatric-type GIST |
| Gender distribution | about 48% female | about 85% female |
| Site of primary | anywhere in the GI tract (and elsewhere in the abdomen) | Usually stomach |
| Presentation | single primary site | May present with multiple stomach tumors (not metastases). This is often described as "multifocal" or "multinodular" |
| Metastasis to lymph nodes | very rare | common |
| Growth | more aggressive | less aggressive |
| Typical histology | spindle-shaped | epithelioid shape (more rounded and similar to the shape of other, non-sarcoma cancers) |
| Response to imatinib | high response rate | Has an undefined; but generally believed to be lower, response rate |
| Mutations | KIT (75%) PDGFRA (8%) |
85% wild-type GIST (no KIT or PDGFRA mutations). There are exceptions to this however (especially in boys) and mutational testing is available. SDH mutations and SDHB inactivation even in the absence of SDH mutations IGF1R overexpression |
Pediatric GIST
Although the exact incidence is still somewhat unclear, it is now estimated that, in the United States, between 4,000 and 6,000 people each year develop GISTs. GISTs occurring in young patients (under age 18) is much rarer, occurring in perhaps 1% to 2% of all GIST patients1 2.
Pediatric GIST has been considered to be a subset of adult GIST. There are however, important differences between adult GIST and pediatric GIST. The risk of recurrence is less predictable in pediatric GIST; the biology is different, the clinical course of the disease is different and the effectiveness of treatments are different. It is important for patients to recognize that the medical team that treats adult GIST (even experienced GIST doctors) may not be the optimal team to treat pediatric GIST.
See the Pediatric GIST section
Familial GIST
The vast majority of patients with GIST did not inherit mutations that cause GIST from their parents. Instead the initiating mutation, typically in the KIT gene but sometimes in the PDGFRA gene, developed in one or more cells sometime during their life. This mutation started a chain of events that eventually developed into GIST. Importantly, the KIT or PDGFRA mutations occur only in the tumor cells. The rest of the cells in the body have KIT and PDGFRA genes, but they are not mutated.
People with familial GIST inherit a mutated gene from one of their parents. It is a very rare type of GIST that affects up to two dozen families in the world (this number is subject to change as we learn more about GIST). Unlike sporadic GIST, people with familial GIST have KIT or (in one case) PDGFRA mutations in every cell in their body. Some patients have a familial form of pediatric GIST caused by mutations in one of the SDH genes.
eGISTs
eGIST is a relatively new term being used to describe rare GISTs in which the primary tumor is believed to occur outside of the GI tract. Because the treatment of GISTs is very different than other tumors that may be confused with eGISTs, it is imperative that an accurate diagnosis be made.
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, Michael P. LaQuaglia, MD, Peter Besmer, PhD, and Cristina R. Antonescu, MD
2. 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
3. Insulin-like growth factor 1 receptor is a potential
therapeutic target for gastrointestinal stromal tumors
Chi Tarn, Lori Rink, Erin Merkel, Douglas Flieder, Harsh Pathak, Daphne Koumbi, Joseph R. Testa,
Burton Eisenberg, Margaret von Mehren, and Andrew K. Godwin
PNAS | June 17, 2008 | vol. 105 | no. 24 | 8387–8392
