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Gastrointestinale Stromatumoren

Eine morphologisch und molekular eigenständige Tumorentität mit neuer therapeutischer Perspektive

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Zusammenfassung

Neuere morphologische und molekulare Befunde haben unser Verständnis über gastrointestinale Stromatumoren (GIST) beträchtlich erweitert. Gastrointestinale Stromatumoren werden gegenwärtig über ihre Überexpression von CD117 (KIT), dem Rezeptor des Stammzellfaktors, definiert und so gegenüber glattmuskulären Tumoren abgegrenzt. Zytogenetisch sind GIST bereits in frühen Stadien durch häufige komplette oder partielle Verluste der Chromosomen 14 und 22 und terminale Deletionen des Chromosomenarms 1p charakterisiert. Im Verlauf der Tumorprogression wird eine Akkumulation von zusätzlichen chromosomalen Anomalien beobachtet. Basierend auf der Erstbeschreibung von aktivierenden KIT-Mutationen in GIST haben sich zahlreiche Studien mit der Rolle von wildtypischem und mutiertem KIT in GIST beschäftigt. Inzwischen wurden in der überwiegenden Mehrheit der GIST KIT-Mutationen identifiziert und selbst in KIT-Mutation-negativen GIST eine konstitutive Phosphorylierung der KIT-Rezeptor-Tyrosinkinase nachgewiesen. Diese Befunde lassen darauf schließen, dass KIT eine zentrale Rolle bei der Pathogenese von GIST spielt. Imatinib (STI571/Glivec®) inhibiert selektiv die BCR/ABL-, die PDGFR- und die KIT-Rezeptor-Tyrosinkinasen. Erste therapeutische Anwendungen von Imatinib bei Patienten mit progredienten GIST haben in dieser chemo- und radiotherapieresistenten Tumorentität beachtliche Ergebnisse erzielt. In dieser Übersicht werden die morphologischen Befunde und molekularen Grundlagen von GIST dargestellt, die eine neue therapeutische Perspektive eröffnet haben.

Summary

Recent morphological and molecular genetic findings have greatly expanded our understanding of gastrointestinal stromal tumors (GISTs). GISTs are now defined by their overexpression of CD117 (KIT), the receptor for the stem cell factor, and can thus be discriminated from smooth muscle tumors. Cytogenetically, GISTs are characterized even in early lesions by frequent entire or partial loss of the chromosomes 14 and 22 and terminal deletions of the chromosomal arm 1p. During tumor progression further chromosomal imbalances accumulate. Following the first report on activating KIT mutations in GISTs, several studies have addressed the role of wild-type and mutant KIT in GISTs and demonstrated activating KIT mutations in the majority of cases. Moreover, KIT tyrosine phosphorylation is even present in KIT mutation-negative GISTs, implicating KIT activation as a central event in the pathogenesis of GISTs. Imatinib (STI571/Glivec®) is a selective inhibitor of BCR/ABL, PDGFR and KIT receptor-tyrosine kinases. First therapeutic applications of imatinib in patients with progressive GISTs have yielded promising results. This review focusses on the morphological and molecular findings in GISTs which have opened up a new therapeutic perspective.

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Literatur

  1. Amin MB, Chan KMA, Linden MD, Kubus JJ, Zarbo RJ (1993) Prognostic value of proliferating cell nuclear antigen index in gastrointestinal stromal tumors: correlation with mitotic count and clinical outcome. Am J Clin Pathol 100:428–432

    CAS  PubMed  Google Scholar 

  2. Appelman HD (1986) Smooth muscle tumors of the gastrointestinal tract: what we know now that Stout didn't know. Am J Surg Pathol 10 [Suppl 1]:83–99

    Google Scholar 

  3. Appelman HD (1990) Mesenchymal tumors of the gut: histological perspectives, new approaches, new results, and does it make any difference? Monogr Pathol 31:220–246

    PubMed  Google Scholar 

  4. Brainard JA, Goldblum JR (1997) Stromal tumors of the jejunum and ileum: a clinicopathologic study of 39 cases. Am J Surg Pathol 21:407–416

    Article  CAS  PubMed  Google Scholar 

  5. Breiner JA, Meis-Kindblom J, Kindblom LG, McComb E, Liu J, Nelson M, Bridge JA (2000) Loss of 14q and 22q in gastrointestinal stromal tumors (pacemaker cell tumors). Cancer Genet Cytogenet 120:111–116

    Article  CAS  PubMed  Google Scholar 

  6. Carney JA (1999) Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney triad): natural history, adrenocortical component, and possible familial occurence. Mayo Clin Proc 74:543–552

    CAS  PubMed  Google Scholar 

  7. Carrillo R, Candia A, Rodriguez-Peralto JL, Caz V (1997) Prognostic significance of DNA ploidy and proliferative index (MIB-1 index) in gastrointestinal stromal tumors. Hum Pathol 28:160–165

    CAS  PubMed  Google Scholar 

  8. Cook JR, Dehner LP, Collins MH, Ma Z, Morris SW, Coffin CM, Hill DA (2001) Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 25:1364–1371

    CAS  PubMed  Google Scholar 

  9. Corless CL, McGreevey L, Haley A, Town A, Heinrich MC (2002) KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567–1572

    CAS  PubMed  Google Scholar 

  10. Cunningham RE, Federspiel BH, McCarthy WF, Sobin LH, O'Leary TJ (1993) Predicting prognosis of gastrointestinal smooth muscle tumors. Role of clinical and histologic evaluation, flow cytometry, and image cytometry. Am J Surg Pathol 17:588–594

    CAS  PubMed  Google Scholar 

  11. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF (2000) Two hundred gastrointestinal stromal tumors. Recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58

    Article  CAS  PubMed  Google Scholar 

  12. DeMatteo RP, Heinrich MC, El-Rifai WM, Demetri G (2002) Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 33:466–477

    Article  CAS  PubMed  Google Scholar 

  13. Demetri GD, Mehren M von, Blanke CD et al. (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480

    Article  CAS  PubMed  Google Scholar 

  14. Druker NJ, Talpaz M, Resta DJ et al. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    CAS  PubMed  Google Scholar 

  15. El-Naggar AK, Ro JY, McLemore D, Garnsey L, Ordoñez N, MacKay B (1989) Gastrointestinal stromal tumors: DNA flow-cytometric study of 58 patients with at least five years of follow-up. Mod Pathol 2:511–515

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. El-Rifai W, Sarlomo-Rikala M, Andersson LC, Miettinen M, Knuutila S (2000b) High-resolution deletion mapping of chromosome 14 in stromal tumors of the gastrointestinal tract suggests two distinct tumor suppressor loci. Genes Chromosomes Cancer 27:387–391

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Franquemont DW (1995) Differentiation and risk assessment of gastrointestinal stromal tumors. Am J Clin Pathol 103:41–47

    CAS  PubMed  Google Scholar 

  20. Fuller CE, Williams GT (1991) Gastrointestinal manifestations of type 1 neurofibromatosis (von Recklinghausen's disease). Histopathology 19:1–11

    CAS  PubMed  Google Scholar 

  21. Gibson PC, Cooper K (2002) CD117(KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 9:65–69

    PubMed  Google Scholar 

  22. Goldblum JR, Appelman HD (1995) Stromal tumors of the duodenum. Am J Surg Pathol 19:71–80

    Google Scholar 

  23. Gunawan B, Bergmann F, Höer J, Langer C, Schumpelick V, Becker H, Füzesi L (2002) Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors. Hum Pathol 33:316–321

    Article  PubMed  Google Scholar 

  24. Haque S, Dean PJ (1992) Stromal neoplasms of the rectum and anal canal. Hum Pathol 23:762–767

    CAS  PubMed  Google Scholar 

  25. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Ziegler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI571, a selective tyrosine kinase inhibitor. Blood 96:925–932

    CAS  PubMed  Google Scholar 

  26. Hirota S, Isozaki K, Moriyama Y et al. (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580

    CAS  PubMed  Google Scholar 

  27. Hirota S, Nishida T, Isozaki K, Taniguchi M, Nakamura J, Okazaki T, Kitamura Y (2001) Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J Pathol 193:505–510

    Article  CAS  PubMed  Google Scholar 

  28. Hirota S, Nishida T, Isozaki K et al. (2002) Familial gastrointestinal stromal tumors associated with dysphagia and novel germline mutation of KIT gene. Gastroenterology 122:1493–1499

    PubMed  Google Scholar 

  29. Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stroma tumor. N Engl J Med 344:1052–1056

    CAS  PubMed  Google Scholar 

  30. Kim N-G, Kim JJ, Ahn L-Y, Seong C-M, Noh SH, Kim CB, Min JS (2000) Putative chromosomal deletions on 9p, 9q and 22q occur preferentially in malignant gastrointestinal stromal tumors. Int J Cancer 85:633–638

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Lasota J, Jasinski M, Sarlomo-Rikala M et al. (1999) 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 154:53–60

    CAS  PubMed  Google Scholar 

  33. Lasota J, Wozniak A, Sarlomo-Rikala M et al. (2000) Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors: a study of 200 cases. Am J Pathol 157:1091–1095

    CAS  PubMed  Google Scholar 

  34. Lee JR, Joshi V, Griffin JW, Lasota J, Miettinen M (2001) Gastrointestinal autonomic nerve tumor. Immunohistochemical and molecular identity with gastrointestinal stromal tumor. Am J Surg Pathol 25:979–987

    CAS  PubMed  Google Scholar 

  35. Lehnert T (1998) Gastrointestinal sarcoma (GIST)—a review of surgical management. Ann Chir Gynaecol 87:297–305

    PubMed  Google Scholar 

  36. Mechtersheimer G, Otaño-Joos M, Ohl S, Benner A, Lehnert T, Willeke F, Möller P, Otto HF, Lichter P, Joos S (1999) Analysis of chromosomal imbalances in sporadic and NF1-associated peripheral nerve sheath tumors by comparative genomic hybridisation. Genes Chromosomes Cancer 25:362–369

    Article  CAS  PubMed  Google Scholar 

  37. Mechtersheimer G, Otaño-Joos M, Freier K, Rieker R, Schwarzbach M, Willeke F, Lehnert T, Lichter P, Otto HF, Joos S (2000) Different patterns of DNA copy number changes in gastrointestinal stromal sarcomas, leiomyosarcomas, and malignant peripheral nerve sheath tumors. Pathol Res Pract 196:389, a174

    Google Scholar 

  38. Miettinen M (2001) Are desmoid tumors kit positive? Am J Surg Pathol 25:549–550

    Article  CAS  PubMed  Google Scholar 

  39. Miettinen M, Lasota J (2001) Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 438:1–12

    CAS  PubMed  Google Scholar 

  40. Miettinen M, Monihan JM, Sarkomo-Rikala M, Kovatich AJ, Carr NJ, Emory TS, Sobin LH (1999) Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol 23:1109–1118

    CAS  PubMed  Google Scholar 

  41. Miettinen M, Blay JY, Sobin LH (2000a) Mesenchymal tumours of the stomach. In: Hamilton SR, Aaltonen LA (eds) World Health Organization classification of tumours. Pathology and genetics of the digestive system, 1st edn. IARC Press, Lyon, France, pp 62–65

  42. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J (2000b) Esophageal stromal tumors. A clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Am J Surg Pathol 24:211–222

    Article  CAS  PubMed  Google Scholar 

  43. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J (2000c) Gastrointestinal stromal tumors and leiomyosarcomas in the colon. Am J Surg Pathol 24:1339–1352

    CAS  PubMed  Google Scholar 

  44. Miettinen M, Sobin L, Sarlomo-Rikala M (2000d) Immunohistochemical spectrum of GISTs at different sites and their differential diagnosis with a reference to CD117 (KIT). Mod Pathol 13:1134–1142

    CAS  PubMed  Google Scholar 

  45. Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J (2001) Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 25:1121–1133

    Article  CAS  PubMed  Google Scholar 

  46. Moyana TN, Freisen R, Tan LK (1991) Colorectal smooth-muscle tumors: a pathologic study with immunohistochemistry and histomorphometry. Arch Pathol Lab Med 115:1016–1021

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Oosterom AT van, Judson I, Verwej J, Stroobants S, Paola ED di, Dimitrijevic S, Martens M, Webb A, Sciot R, Glabbeke M van, Silberman S, Nielsen OS (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423

    Article  PubMed  Google Scholar 

  49. Otaño-Joos M, Mechtersheimer G, Ohl S, Wilgenbus KK, Scheurlen W, Lehnert T, Willeke F, Otto HF, Lichter P, Joos S (2000) Detection of chromosomal imbalances in leiomyosarcoma by comparative genomic hybridization and interphase cytogenetics. Cytogenet Cell Genet 90:86–92

    Article  PubMed  Google Scholar 

  50. Reith JD, Goldblum JR, Lyles RH, Weiss SW (2000) Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 13:577–585

    CAS  PubMed  Google Scholar 

  51. Robinson TL, Sircar K, Hewlett BR, Chorneyko K, Riddell RH, Huizinga JD (2000) Gastrointestinal stromal tumors may originate from a subset of CD34-positive interstitial cells of Cajal. Am J Pathol 156:1157–1163

    CAS  PubMed  Google Scholar 

  52. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen C-J, Xiao S, Tuveson DA, Demetri GD, Fletcher CDM, Fletcher JA (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121

    CAS  PubMed  Google Scholar 

  53. Rudolph P, Gloeckner K, Parwaresch R, Harms D, Schmidt D (1998) Immunophenotype, proliferation, DNA ploidy, and biological behaviour of gastrointestinal stromal tumors: a multivariate clinicopathologic study. Hum Pathol 29:791–800

    CAS  PubMed  Google Scholar 

  54. Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M (1999a) Embryonic form of smooth muscle myosin heavy chain (Smemb/MHC-B) in gastrointestinal stromal tumor and interstitial cells of Cajal. Am J Pathol 154:23–28

    CAS  PubMed  Google Scholar 

  55. Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M (1999b) C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res 90:1321–1328

    CAS  PubMed  Google Scholar 

  56. Sarlomo-Rikala M, El-Rifai W, Andersson L, Miettinen M, Knuutila S (1998a) Different patterns of DNA copy number changes in gastrointestinal stromal tumors, leiomyomas and schwannomas. Hum Pathol 29:476–481

    CAS  PubMed  Google Scholar 

  57. Sarlomo-Rikala M, Kovatich AJ, Barusevisius A, Miettinen M (1998b) CD117. A sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 11:728–734

    CAS  PubMed  Google Scholar 

  58. Sbaschnig RJ, Cunningham RE, Sobin LH et al. (1994) Proliferating-cell nuclear antigen immunohistochemistry in the evaluation of gastrointestinal smooth-muscle tumors. Mod Pathol 7:780–783

    CAS  PubMed  Google Scholar 

  59. Schmidt H, Würl P, Taubert H, Meye A, Bache M, Holzhausen H-J, Hinze R (1999) Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant. Genes Chromosomes Cancer 25:205–211

    Article  CAS  PubMed  Google Scholar 

  60. Sreekantaiah C, Davis JR, Sandberg AA (1993) Chromosomal abnormalities in leio-myosarcomas. Am J Pathol 142:293–305

    CAS  PubMed  Google Scholar 

  61. Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H, Kitamura Y (1999) Effect of c-kit mutations on prognosis of gastrointestinal stromal tumors. Cancer Res 59:4297–4300

    CAS  PubMed  Google Scholar 

  62. Tsujimura T, Makiishi-Shimobayashi C et al. (2001) Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol 158:817–823

    CAS  PubMed  Google Scholar 

  63. Tworek JA, Appelman HD, Singleton TP et al. (1997) Stromal tumors of the jejunum and ileum. Mod Pathol 10:200–209

    CAS  PubMed  Google Scholar 

  64. Tworek JA, Goldblum JR, Weiss SW, Greenson JK, Appelman HD (1999a) Stromal tumors of the abdominal colon. A clinicopathologic study of 20 cases. Am J Surg Pathol 23:937–945

    CAS  PubMed  Google Scholar 

  65. Tworek JA, Goldblum JR, Weiss SW, Greenson JK, Appelman HD (1999b) Stromal tumors of the anorectum. Am J Surg Pathol 23:946–954

    Article  CAS  PubMed  Google Scholar 

  66. Wardelmann E, Neidt I, Bierhoff E et al. (2002) C-kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid variant. Mod Pathol 15:125–136

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Pathologisches Institut, Universität Heidelberg

    G. Mechtersheimer, R. Penzel & H. F. Otto

  2. Chirurgische Universitätsklinik Heidelberg

    T. Lehnert

  3. Abt. Molekulare Genetik, Deutsches Krebsforschungszentrum Heidelberg

    S. Joos

  4. Medizinische Klinik V, Universität Heidelberg

    G. Egerer

  5. Pathologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Deutschland

    G. Mechtersheimer

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  1. G. Mechtersheimer
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  2. T. Lehnert
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  3. R. Penzel
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  4. S. Joos
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  5. G. Egerer
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  6. H. F. Otto
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Mechtersheimer, G., Lehnert, T., Penzel, R. et al. Gastrointestinale Stromatumoren. Pathologe 24, 182–191 (2003). https://doi.org/10.1007/s00292-003-0612-2

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