biomedical informatics cover Perl Programming for Medicine and Biology Cover

Biomedical Informatics books
by Jules J. Berman

  • Jones & Bartlett sales and informational website for Biomedical Informatics
  • Amazon.com U.S. book site for Biomedical Informatics
  • Full Table of Contents from Library of Congress for Biomedical Informatics
  • List of book-related resources
  • Brief author biography on Association for Pathology Informatics Website
  • Quick link to PubMed listing for Jules J. Berman
  • Full list of Publications for Jules J. Berman
  • Dr. Bruce Friedman's review of Biomedical Informatics
  • Perl Programming for Medicine and Biology companion site.
  • Author's blog on data specifications
  • Contact author







  • Gastrointestinal Stromal Tumors (GIST): Answers and Questions

    Published as:
    Gastrointestinal stromal tumors: answers and questions.
    Hum Pathol. 2002 May;33(5):456-458.
    PMID: 12094369
    






    Timothy O'Leary, Ph.D., M.D.1 and Jules J. Berman, Ph.D., M.D.2





    1Department of Cellular Pathology and Genetics

    Armed Forces Institute of Pathology

    Washington, DC 20306-6000

    2Cancer Diagnosis Program

    National Cancer Institute

    National Institutes of Health

    Rockville, MD 20892

    Address for Correspondence:

    Timothy J. O'Leary

    Department of Cellular Pathology and Genetics

    Armed Forces Institute of Pathology

    Washington, DC 20306-6000

    Phone: 301-319-0200

    Facsimile: 301-295-9507

    Email: oleary@afip.osd.mil







    Introduction

    In 1984 Schaldenbrand and Appelman first applied the term "stromal tumor" to refer collectively to a group of mesenchymal neoplasms that have been referred to by several names pertaining to neurogenic or myogenic differentiation 1. Most of these tumors demonstrated some features typical of smooth muscle differentiation, and had been referred to as leiomyomas or leiomyosarcomas. Gradually the term GIST (for gastrointestinal stromal tumor) came into widespread use, reflecting both uncertainty over the histogenesis of this tumor, as well as the difficulties sometimes associated with predicting the probability of malignant behavior.

    In the past few years, we have learned a bit. We now know that the cells in GIST demonstrate characteristics similar to those of the interstitial cell of Cajal, or "pacemaker cell" which has a neuromotor role in normal gut motility. Interstitial cells of Cajal are characterized by expression of KIT. An immunohistochemical marker (CD-117) for KIT is now used by pathologists to distinguish GISTs from non-GIST spindles tumors occurring in the GI tract. Mutations in the KIT gene lead to overexpression of the tyrosine kinase moiety of the KIT protein. Heightened tyrosine kinase activity appears to drive the neoplastic growth of GISTs. STI-571 (Gleevec ®, Novartis, Basel) inhibits KIT tyrosine kinase activity, enabling an attack on a specific molecular target in GISTs. Early clinical trials with STI-571 resulted in remarkable remissions of metatatic GIST, a tumor that was resistant to all prior forms of chemotherapy 2,3. One result is that GISTs now serve as the model solid tumor for a molecular-biology-based diagnosis and treatment of cancer.

    This article explores some of our knowledge about GIST and serves as introduction to four articles in this special issue of Human Pathology. These articles were planned at a GIST workshop held at NIH on April 2-3, 2001, that was jointly sponsored by the NIH Office of Rare Diseases and by the Armed Forces Institute of Pathology 4. These articles provide state-of-the-art reviews of GIST diagnosis (Chris Fletcher et al), treatment (Ronald DeMatteo et al), prognosis (Markku Miettinen et al.) and genetics (Jonathan Fletcher et al.). A common theme among these articles is the expanded role of the pathologists in an age of molecular targets for diagnosis and treatment.

    The Role of the Pathologist in GIST Diagnosis

    Despite remarkable progress in understanding and treating GIST, pathologists still have difficulty predicting which GISTs will metastasize. Of those GISTs which undergo resection, about half will recur or metastasize, and the half will not 5. While large size and high mitotic activity have been strongly associated with malignancy in tumors arising throughout the gastrointestinal tract, small size and the absence of mitotic activity have not precluded malignant behavior. Despite histologic similarities, clinical behavior has differed substantially among tumors arising at different locations along the gastrointestinal tract. A variety of adjunct diagnostic techniques , including flow and image cytometry and immunohistochemical assessment of cell cycle proteins have been used in attempts to improve the accuracy of outcome prediction. Although the results of these early approaches were disappointing, subsequent molecular investigations led to new insights, and eventually to improved treatment.

    Subsequent to the observation that KIT protein (CD117) is highly expressed in GIST 6,7, Hirota and his coworkers observed exon 11 mutations in several GISTs 8. These mutations resulted in constitutive activation of the tyrosine kinase activity of the KIT protein; KIT activation also characterizes GISTs that lack KIT mutation 9. Shortly thereafter, several investigators showed an association between KIT mutations in GIST and malignant phenotype in GIST tumors 10,11.

    The almost synchronous observation that a small molecule could inhibit the tyrosine kinase activity of KIT quickly led to its therapeutic use in a woman who had undergone several resections for metastatic GIST, and who still harbored a substantial tumor burden 2. A remarkable reduction of tumor load followed, together with histologic evidence of widespread tumor cell necrosis. Subsequent clinical investigations have amply demonstrated that this was not an isolated event 3.

    If all GISTs demonstrated KIT mutations and responded to Gleevec ®, GIST would provide an ideal model of how cancer diagnosis and therapy should be coupled in the era of molecular medicine. Unfortunately, neither is true. Although most patients demonstrate responses to the drug, not all do; furthermore, it is not yet clear how durable responses will be. It may be that KIT, like ABL (another tyrosine kinase that is inhibited by Gleevec ®, enabling treatment of chronic myelogenous leukemia 12-14) can undergo amplification or mutation resulting in a loss of the drug's effectiveness15. If so, a much better understanding of the pathogenesis of GIST will be required to enable effective long-term treatment.

    There are, in fact, many unanswered questions regarding GIST pathogenesis. Among the many unanswered questions of pathogenesis are the following.

    1. What are the molecular changes in benign GISTs. Several molecular and cytogenetic investigations suggest a relationship between changes on 9p and the development of benign GISTs.

    2. Are malignant GISTs malignant from their inception, or can they arise from preexisting benign tumors?

    3. Although KIT mutation may be sufficient to confer a malignant phenotype, it is clearly not required. Several studies suggest that nearly half of malignant GISTs do not demonstrate KIT mutations 10,11,16. Do these tumors demonstrate mutation or abnormal regulation of genes coding for other proteins in the KIT pathway, or are unrelated events on other chromosomes sufficient to confer malignancy?

    4. What are the downstream events that result from constitutive activation of KIT in GISTs? Do these differ from other tumors in which KIT is overexpressed? Do changes in the relative expressions of the short and long KIT transcript isoforms 17 have significance for pathogenesis or progrnosis?

    5. Many chromosomal and other genetic alterations have been observed in GIST (Table 1). Are these changes directly involved in pathogenesis, or are they a result of faulty regulation/repair?

    6. Do the stromal tumors arising in children with the Carney triad of GIST, pulmonary chondroma and extra-adrenal paraganglioma 18 result from the same genetic abnormalities as those accompanying their sporadic counterparts?

    Practical questions regarding routine diagnosis and therapy also remain, and must be thoroughly addressed before optimal treatment can be assured.

    1 Are the various immunohistochemical assays for the KIT protein equivalent? If staining for KIT is to be the major criterion by which decisions as to Gleevec ® therapy is to be given, efforts must be made to assure that the immunoistochemical assay employed is the assay which is most effective in identifying patients likely to respond to this therapy. This requires clinical trials - not simply a consensus opinion among pathologists or clinicians as to which assay is "best.

    1 Should Gleevec ® be given to patients who do not demonstrate evidence of KIT activation, such as mutation?

    2 Is Gleevec ® therapy most effective when given to patients with advanced disease, or should it be given early in the course of treatment? Should it be given to patients with small, gastric, mitotically indolent tumors that are unlikely to metastasize?

    3 How should the likelihood of metastasis be assessed? Is KIT gene mutation independently predictive of outcome when tumor location, size, and mitotic index are considered?

    Answering these questions and other like it will require cooperation of investigators in many institutions. We urge the investigators in clinical trials to make tissues available to basic scientists who may not be associated with clinical trial institutions, and those with large archival resources to share them widely and wisely. Early interchange of data should be encouraged; informal exchange of with large numbers of investigators should be encouraged by scientific journals, rather than being treated as "prior publication." By means of such cooperative enterprises the rapid advances which have been made in the definition, diagnosis and definitive treatment of GIST can indeed become a model for the future development of molecular medicine.

    Conclusions

    Now and in the future, pathologists will play a vital role in the emerging world of molecular medicine. Pathologists will be expected to include specific prognostic and predictive information in their diagnostic reports. They will be expected to order ancillary tests (e.g. molecular diagnostic tests or tests using predictive markers) as appropriate and to contribute their expertise towards national (and even international) clinical trials. Sometimes this may require pathology departments to save and annotate tissues according to highly specific protocols and to work closely with a wide variety of clinician/scientists. Perhaps most importantly, pathologists will be the first ones to encounter the cases where tumors do not respond as predicted, nothing seems to fit the experimental model, and further investigation s required to better define new approaches to diagnosis and therapy.

    References:

    1. Schaldenbrand JD, Appelman HD. Solitary solid stromal gastrointestinal tumors in von Recklinghausen's disease with minimal smooth muscle differentiation. Hum.Pathol. 1984; 15:229-232.

    2. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N.Engl.J.Med.2001;344:1052.-6.

    3. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato dP, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001: 358:1421-1423.

    4. Berman J, O'Leary TJ. Gastrointestinal stromal tumor workshop. Hum.Pathol.2001 32:578-582.

    5. Emory TS, Sobin LH, Lukes L, Lee DH, O'Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am.J.Surg.Pathol. 1999; 23:82-87.

    6. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod.Pathol. 1998; 11:728-734.

    7. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am.J.Pathol. 1998; 152:1259-1269.

    8. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279:577-580.

    9. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz A, et al. KIT activation is a ubiquitous feature of gastrointestinal sromal tumors. Cancer Res. 2001; 61:8118-8121.

    10. Ernst SI, Hubbs AE, Przygodzki RM, Emory TS, Sobin LH, O'Leary TJ. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. Lab.Invest. 1998; 78:1633-1636.

    11. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am.J.Pathol. 1999; 154:53-60.

    12. Kasper B, Fruehauf S, Schiedlmeier B, Buchdunger E, Ho AD, Zeller WJ. Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors. Cancer Chemother.Pharmacol. 1999; 44:433-438.

    13. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000.Sep.15.;289.(5486.):1938.-42. 289:1938-1942.

    14. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J.Clin.Invest.2000; 105:3-7.

    15. Barthe C, Cony-Makhoul P, Melo JV, Mahon JR. Roots of clinical resistance to STI-571 cancer therapy. Science 2001; 293:2163

    16. Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 1999; 59:4297-4300.

    17. Andersson J, Sjogren H, Meis-Kindblom JM, Stenman G, Aman P, Kindblom LG. The complexity of KIT gene mutation and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors. Am.J.Pathol. 2002; 160:15-22.

    18. Carney JA. The triad of gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma. Cancer 1979; 43:374-382.

    19. Sreekantaiah C, Davis JR, Sandberg AA. Chromosomal abnormalities in leiomyosarcomas. Am.J.Pathol. 1993; 142:293-305.

    20. O'Leary T, Ernst S, Przygodzki R, Emory T, Sobin L. Loss of heterozygosity at 1p36 predicts poor prognosis in gastrointestinal stromal/smooth muscle. Lab.Invest. 1999; 79:1461-1467.

    21. Nilbert M, Mandahl N, Heim S, Rydholm A, Helm G, Willen H, et al. Complex karyotypic changes, including rearrangements of 12q13 and 14q24, in two leiomyosarcomas. Cancer Genet.Cytogenet. 1990; 48:217-223.

    22. Sait SN, Dal Cin P, Sandberg AA. Consistent chromosome changes in leiomyosarcoma. Cancer Genet.Cytogenet. 1988; 35:47-50.

    23. Bardi G, Johansson B, Pandis N, Heim S, Mandahl N, Bak-Jensen E, et al. Recurrent chromosome aberrations in abdominal smooth muscle tumors. Cancer Genet.Cytogenet. 1992; 62:43-46.

    24. Becher R, Wake N, Gibas Z, Ochi H, Sandberg AA. Chromosome changes in soft tissue sarcomas. J.Natl Cancer Inst. 1984; 72:823-831.

    25. Knuutila S, Armengol G, Bjorkqvist AM, El-Rifai W, Larramendy ML, Monni O, et al. Comparative genomic hybridization study on pooled DNAs from tumors of one clinical-pathological entity. Cancer Genet.Cytogenet. 1998; 100:25-30.

    26. El-Rifai W, Sarlomo-Rikala M, Miettinen M, Knuutila S, Andersson LC. DNA copy number losses in chromosome 14: an early change in gastrointestinal stromal tumors. Cancer Res. 1996; 56:3230-3233.

    27. Mandahl N, Fletcher CD, Dal Cin P, De Wever I, Mertens F, Mitelman F, et al. Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group. Cancer Genet.Cytogenet. 2000;116:66-73.

    28. El-Rifai W, Sarlomo-Rikala M, Andersson LC, Knuutila S, Miettinen M. DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance. Cancer Res.2000; 60:3899-3903.

    29. Marci V, Casorzo L, Sarotto I, Dogliani N, Milazzo MG, Risio M. Gastrointestinal stromal tumor, uncommitted type, with monosomies 14 and 22 as the only chromosomal abnormalities. Cancer Genet.Cytogenet. 1998; 102:135-138.

    30. Sarlomo-Rikala M, El-Rifai W, Lahtinen T, Andersson LC, Miettinen M, Knuutila S. Different patterns of DNA copy number changes in gastrointestinal stromal tumors, leiomyomas, and schwannomas. Hum.Pathol. 1998; 29:476-481.

    31. Boghosian L, Dal Cin P, Turc-Carel C, Rao U, Karakousis C, Sait SJ, et al. Three possible cytogenetic subgroups of leiomyosarcoma. Cancer Genet.Cytogenet. 1989; 43:39-49.



    Table 1

    Selected Alterations in Gastrointestinal Stromal Tumors

    Chromosomal Locus Type of Study Finding References
    1p35-36 Cytogenetics* Rearrangement 17,19
    1p35-36 LOH LOH in about 1/3 of cases 20
    1p32 Cytogenetics Rearrangement 21
    1p13 Cytogenetics Deletion 22
    LOH LOH in about 1/3 of cases 20
    1q32 Cytogenetics Rearrangement 23,24
    4q12 DNA Sequencing KIT Mutation 8
    5p Comparative genomic hybridization Amplification 25,26
    7p11.1-21 Cytogenetics Rearrangement 27
    7q32 Cytogenetics Rearrangement 19
    8q22 Comparative genomic hybridization Amplification 25,26
    9p CGH Loss 28
    9q Comparative genomic hybridization Deletion 26
    10q22 Cytogenetics Rearrangement 19
    13q14 Cytogenetics Rearrangement 19
    14 Cytogenetics Frequent monosomy 23,29
    14q22 Comparative genomic hybridization Loss 26
    17q22 Comparative genomic hybridization Amplification 30
    18 Cytogenetics Frequent monosomy 31
    19q13 Comparative genomic hybridization Amplification 25
    22 Cytogenetics Frequent monosomy 17,23,29
    22q12 Comparative genomic hybridization Loss 30


    * The cytogenetic studies may include some findings from tumors that would now be classified as leiomyosarcomas.

    biomedical informatics cover Perl Programming for Medicine and Biology Cover