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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4682-4683 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.6680
Chronic Myeloid Leukemia and Gastrointestinal Stromal Tumor: Simultaneous PresentationCancer and Blood Specialists of Nevada, Las Vegas, NV
Department of Leukemia and Lymphoma, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Department of Sarcoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX The patient was a previously healthy 63-year-old man who presented with a recent onset lethargy and a 12-pound weight loss. The patient was initially found to have a WBC count of 19,000/µL, hemoglobin of 8.6 gm/dL, hematocrit of 27.0%, and a platelet count of 735. A computed tomographic (CT) scan revealed massive splenomegaly and a heterogeneous soft tissue mass in the midabdomen, measuring 20 x 13.5 x 24 cm in craniocaudal dimension. Bone marrow aspirate and biopsy were consistent with chronic myeloid leukemia (Fig 1). 18/20 cells were characterized by a 46 XY translocation (9;22) (q34;q11.2) [18/45X-Y]. The bone marrow was 100% hypercellular. The patient was initiated on imatinib mesylate (IM) 100 mg by mouth four times per day.1-4 The patient was subsequently admitted to the hospital secondary to fever. The previously described abdominal mass was identified by CT and found to have central necrosis. He underwent resection of both the abdominal mass and his spleen. The 25-cm abdominal mass was found to arise from the small intestine and was histologically classified as a gastrointestinal stromal tumor (GIST).5 At laparotomy, the GIST presented as a protuberant, glistening mass (Fig 2). The GIST was adherent to the spleen (Fig 3). On histologic evaluation, the tumor was noted to have four mitiotic figures per 10 high powered fields and stained for vimentin by immunohistochemistry. The GIST was composed of palisading spindled cells without evidence of necrosis (Figs 4 and 5; low power and high-powered view of GIST). The tumor size (> 10 cm) and the mitotic rate meet the criteria for high risk of recurrence.6 KIT mutational analysis was performed on the resected GIST revealing a 15-base pair in-frame deletion spanning codons 551 to 555 in exon 11 as well as a point mutation at codon 550 resulting in isoleucine (ATA) instead of lysine (AAA). Mutation in exon 11 has been shown to be the most favorable location for benefit from therapy with IM.7 These two observations, high likelihood of recurrence and high likelihood of benefit from IM, prompted us to treat his GIST with adjuvant IM. The adjuvant versus placebo trial for IM in GIST, ACOSOG Z9001, was recently closed because of superiority of the adjuvant IM (Gleevec; Novartis Pharmaceuticals Corporation, East Hanover, NJ) arm at interim analysis.8 The spleen showed a minimal expansion of the splenic red pulp. Myeloid precursors were seen as well as a mild degree of extramedullary hematopoiesis, consistent with CML, chronic phase. Presence of the Philadelphia chromosome was confirmed.
The patient continues to take IM, 400 mg per day.9-11 The patient continues to do well and CT scans of the abdomen reveal no evidence of disease. Bone marrow aspirate and biopsy completed 6 months after diagnosis were consistent with 20% to 40% cellularity, with no evidence of the Philadelphia chromosome. Fluorescence in situ hybridization utilizing the Vysis LSI BCR/ABL ES probe (Abbott Laboratories, Downers Grove, IL) showed no evidence of the BCR/ABL translocation. He has developed a grade 2 macular skin rash and mild hyperbilirubinemia but otherwise has done well. To our knowledge, there has heretofore never been a report of both of these malignancies occurring in the same individual. Interestingly, the patient's mother died of an unknown type of stomach tumor at the age of 73, but pathology was unavailable for review. We hypothesize that a regional mutation may have occurred enhancing susceptibility to two mesodermally derived tumors (ie, both the GIST and CML). Alternatively, the patient may have a defect in DNA repair machinery that did not appropriately repair the two mutations that led to GIST and CML. Moreover, this patient may have chromosomal instability allowing more frequent translocations or deletions and the two present in this individual simply escaped repair. A unifying hypothesis supports a single underlying genetic instability that could have led to both diseases. In conclusion, this single individual developed two rare malignancies and on molecular analysis was found to have three genetic abnormalities: a small deletion, a point mutation, and a chromosomal translocation. The prevalence and molecular biology behind this finding necessitate additional investigation in a larger set of patients. The occurrence of two malignancies in the same individual, both sensitive to the effects of IM, appears to be an unfortunate event with a fortuitous, single therapy given the excellent control of each disease. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Druker B, Guilhot F, O'Brien S, et al: Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myeloid leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study. J Clin Oncol 24:338s, 2006 (abstr 6506) 2. Goldman JM, Melo JV: Chronic myeloid leukemia –advances in biology and new applications to treatment. N Engl J Med 349:1451-1464, 2003 3. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, et al: Hematologic and cytogenetic resonses to imatinib mesylate in chronic myeloid leukemia. N Engl J Med 346:645-652, 2002 4. Kurzrock R, Kantarjian HM, Druker BJ, et al: Philadelphia chromosome-positive leukemia: Basic mechanisms to molecular therapeutics. Ann Intern Med 138:819-830, 2003 5. Miettinen M: Gastrointestinal stromal tumors (GISTS): Definition, pathology, occurrence and differential diagnosis, in Kitamura Y, Miettinenn M, Hiroto S, et al (eds): Gastrointestinal Stromal Tumor (GIST): From Pathology to Molecular Target Therapy. Tokyo, Japan, Japan Scientific Societies Press, Karger, 2004, pp 3-28 6. Nilsson B, Bumming P, Meis-Kindblom JM, et al: Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era –a population-based study in western Sweden. Cancer 103:821-829, 2005[CrossRef][Medline] 7. Rutkowski P, Nowecki ZI, Debiec-Rychter M, et al: Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+)gastrointestinal stromal tumors (GISTs). J Cancer Res Clin Oncol 133:589-597, 2007[CrossRef][Medline] 8. DeMatteo R, Owzar K, Kaki R, et al: Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. J Clin Oncol 25, 2007 (abstr 10079) 9. Bumming P, Andersson J, Meis-Kindblom JM, et al: Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: A centre-based study of 17 patients. Cancer 89:460-464, 2003 10. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate on gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002 11. Joensuu J, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:105-109, 2001
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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