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Making a Mark, a program of art and creative writing by children touched by cancer
 

 

Texas Children's Cancer Center

 


 

Baylor College of Medicine

In this issue

Director's Corner by David G. Poplack, M.D.

Gastrointestinal stromal tumors (GIST)
by Alberto Pappo, M.D.

Turning the Immune System Against Neuroblastoma
by Doug Myers, M.D. and Malcolm Brenner, M.D., Ph.D.

Pediatric Hematology Oncology Subspecialty
Training in the United States
by Lindsay B. Kilburn, M.D. and C. Philip Steuber, M.D.

Regulatory and Ethical Issues in the Treatment of Children
by Bambi Grilley, R.Ph., C.C.R.P., C.C.R.C., C.I.P., Stacey Berg, M.D.
and Cynthia Boudreaux, M.Ed., C.C.R.P.
     

Gastrointestinal stromal tumors (GIST)
by Alberto Pappo, M.D.

 

  
 

Dr.Alberto Pappo

Figure 1

Gastrointestinal stromal tumors (GIST) are the most common adult mesenchymal tumors of the gastrointestinal tract. The majority of these tumors are characterized by positive Kit immunostaining (CD 117) (Figure 1) and mutations of the KIT or PDGFR genes (Figure 2).1,2 These tumors are presumed to arise from a precursor cell that gives rise to the interstitial cells of Cajal, which normally regulate gastrointestinal motility and autonomic nerve function. In the past, these tumors were misclassified as leiomyoma, leiomyoblastoma, or leiomyosarcoma.

Epidemiology
The estimated age-adjusted yearly incidence of GIST as reported by SEER was 6.8 per million.3 Most reports suggest that there are at least 3,000 cases of GIST diagnosed in the United States each year of which 20 percent to 30 percent are malignant. Most GIST affect adults in their 60s without a specific sex predilection and the majority arise in the stomach (50 percent) (Figure 3) or small bowel (25 percent).4

Clinical presentation

Figure 2
(From Heinrich M. ASCO 2005)
Patients with GIST most often present with gastrointestinal bleeding.2 Other presenting symptoms include a palpable abdominal mass, intestinal obstruction, and acute abdomen. GIST can also be found incidentally at the time of surgery for unrelated issues or at the time of an endoscopy or autopsy. In about 5 percent of cases, GIST are associated with one of three hereditary syndromes which include Carney’s triad (gastric GIST, paraganglioma, pulmonary chondroma) , neurofibromatosis type 1 and familial GIST.2,5,6

Pathology
Most GISTs have one of three histologic patterns comprised of spindle cells (the most common), epithelioid cells, or a mixture of both. About 95 percent of GIST stain positive for KIT (CD117), and is most commonly distributed in the cytoplasm.

Diagnosis

Figure 3
A multidisciplinary team with expertise in sarcomas should ideally care for patients with GIST. The diagnostic workup should include a thorough history and physical examination and computed tomography of the chest, abdomen, and pelvis. Endoscopy should be performed in selected cases and baseline laboratory studies should include a complete blood count and liver function tests. A surgical consult should be obtained to assess tumor resectability.

Prognostic factors
The two most important prognostic features of a primary tumor are its size and mitotic index. GISTs that are 2 cm or less in size can be regarded as essentially benign, but lesions larger than 2 cm have a risk of recurrence.7

KIT and PDGFR Mutations
Approximately 80 percent of GISTs have activating mutations of KIT that most commonly involve the juxtamembrane domain encoded by exon 11 (Figure 2).1 About 5 percent of GIST have activating mutations involving PDGFRA (Figure 2).8 Only about 10 percent of U.S. adult GIST are negative for KIT and PDGFRA gene mutations and are often referred to as "wild-type" GIST. Kinase genotype predicts response to imatinib therapy with patients whose tumors have an exon 11 mutation faring better than those with exon 9 mutations or no mutations.9,10

Treatment
Surgery is the mainstay of therapy for patients with GIST, which are localized and deemed to be resectable. For patients with unresectable or metastatic GIST, response rates to standard chemotherapy regimens are poor.11 For patients with unresectable or metastatic GIST, Imatinib (GLEEVEC) offers clinical benefit (defined as stable disease, and partial and complete responses) in over 80 percent of patients.12,13 For patients who are intolerant or resistant to imatinib, administration of sunitinib has proven to be beneficial and should be strongly be considered.14

Pediatric GIST
Pediatric GIST is extremely rare but accurate estimates of the numbers of children and adolescents diagnosed with this disease are lacking. Single institutions studies and limited reviews suggest that pediatric GIST is biologically different from adult GIST and therefore, the therapeutic strategies used for adults may not be applicable to children.15-18; Pediatric GIST are characterized by a preponderance of cases in females, they primarily occur in the stomach, they are often epithelioid or mixed morphology, have a higher rate of lymph node metastases and tend to be multifocal.15 The majority of pediatric GIST do not have KIT or PDGFR mutations and the few pediatric patients that have been treated with imatinib have failed trespond favorably to this drug.15 However, sunitinib has been successfully used in three pediatric patients who were resistant to imatinib.19 These findings suggest that pediatric patients with GIST should be cared for in specialized centers and that more research is needed to better define the natural histology, biology and best therapies for this disease in children. The GIST center at Texas Children’s Hospital has ample expertise in the treatment and diagnosis of GIST and is comprised of a highly competent multidisciplinary team comprised of f pediatric oncologists, social workers, psychologists, radiologists (with access to CT, MR and PET), radiotherapists (including IMRT and proton beam), and surgeons. In addition, we have an active molecular oncology program, cell biology, and developmental therapeutics program that can help accelerate and facilitate the translation of basic laboratory findings into the clinic.

About the Author
Alberto Pappo, M.D., is a professor of pediatrics at Baylor College
of Medicine and head of the Solid Tumor Program at the Texas Children’s Cancer Center. Dr. Pappo chairs the rare tumor initiative of the Children’s Oncology Group (COG) and is a member of the soft tissue sarcoma committee of COG. His clinical and research interests include soft tissue and bone sarcomas, rare tumors, melanoma and GIST.

References

  1. Corless CL, Fletcher JA, Heinrich MC. Biology of Gastrointestinal Stromal Tumors. J Clin Oncol 2004;22(18):3813-3825.
  2. Miettinen M LJ. Gastrointestinal stromal tumors. Review of morphology, molecular pathology, prognosis and differential diagnosis. Arch Pathol Lab Med 2006;130:1466-1478.
  3. Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol 2005;100(1):162-8.
  4. Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol 2002;3(11):655-64.
  5. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006;30(1):90-6.
  6. Li FP, Fletcher JA, Heinrich MC, et al. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23(12):2735-43.
  7. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006;130(10):1466-78.
  8. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23(23):5357-64.
  9. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21(23):4342-9.
  10. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006;42(8):1093-103.
  11. Clary BM, DeMatteo RP, Lewis JJ, Leung D, Brennan MF. Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison. Ann Surg Oncol 2001;8(4):290-9.
  12. Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39(14):2006-11.
  13. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472-80.
  14. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368(9544):1329-38.
  15. Prakash S, Sarran L, Socci N, et al. 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 2005;27(4):179-87.
  16. Hayahi Y, Okazaki T, Yamataka A, et al. Gastrointestinal stromal tumor in a child and review of the literature. Pediatr Surg Int 2005;21(11):914-7.
  17. Pric V ZM, Smith C, Chilton-Macneill D, Malkin D, pappo A. Clinical and molecular characteristics of pediatric gastrointestinal tumors (GISTs). Proc Amer Soc Clin Oncol 2004, New Orleans, La.
  18. Cypriano MS, Jenkins JJ, Pappo AS, Rao BN, Daw NC. Pediatric gastrointestinal stromal tumors and leiomyosarcoma. Cancer 2004;101(1):39-50.
  19. Janeway KA MD, Butrynski JE, D'Amato GZ, Argesta S, Garret C, Corless CL, Albritton KH, Demetri GD. Sunitinib treatment of pediatric metastatic GIST after failure of Imatinib. American Society of Clinical oncology 2006, Atlanta, GA.
  20. Kuroiwa M, Hiwatari M, Hirato J, et al. Advanced-stage gastrointestinal stromal tumor treated with imatinib in a 12-year-old girl with a unique mutation of PDGFRA. J Pediatr Surg 2005;40(11):1798-801.
  21. Price VE, Zielenska M, Chilton-MacNeill S, Smith CR, Pappo AS. Clinical and molecular characteristics of pediatric gastrointestinal stromal tumors (GISTs). Pediatr Blood Cancer 2005;45(1):20-4.
  22. Miettinen M, Lasota J, Sobin LH. 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 2005;29(10):1373-81.
  23. Bond M BM, Pappo A, Schultz KR, Krailo M, Fouladi M, Hill DA, Heinrich M, Blaney S, Adamson PC. Phase 2 trial of imatinib mesylate (IM) for treatment or recurrent or refractory pediatric solid tumors: A Children's Oncology Group Study. American Society of Clinical Oncology 2005, Orlando, FL.
   

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