Prognostic significance of clinicopathologic parameters in gastrointestinal stromal tumors: a study of 156 cases

Abstract

The biological behavior of gastrointestinal stromal tumors (GISTs) are highly variable. To investigate the biological behavior of GIST, we collected 83 cases of gastric and 62 cases of small intestinal GIST from the Department of Pathology of the Chinese PLA General Hospital. The parameters include age, primary tumor location, tumor diameter, mitotic index, tumor necrosis, risk assessment, clinical stage and the c-kit exon 11 mutation. All these were analyzed in 105 cases along with the follow-up data and tested by log rank and COX hazard proportional model. We find that the average age of gastric GIST was 55.4 years. Of the 62 cases that were followed up, 17 cases had metastasis or recurrence and the 5-year survival rate was (66.51 ± 17.06)%. For the small intestinal GIST, the average age was 50.6 years and 43 cases were followed up. Of these, 22 cases had metastasis or recurrence and the 5-year survival rate was (61.76 ± 18.30)%. Small intestinal GIST was more frequently associated with metastasis and tumor relapse than gastric GIST (?² = 6.131, P = 0.013). For gastric GIST, patients younger than 50 years (P = 0.046), the advanced clinical stage (P = 0.0001), the large tumor diameter (P = 0.0001), a high mitotic index (P = 0.0001), necrosis (P = 0.0001) and a high risk grade (P = 0.004) were all correlated with a lower survival rate. The COX hazard proportional model revealed that advanced clinical stage (P = 0.001), large tumor size (P = 0.001), a high mitotic index (P = 0.002) and the high risk grade (P = 0.018) indicated a poorer prognosis in gastric GIST. For small intestinal GIST, necrosis (P = 0.036) and advanced clinical stage (P = 0.010) were associated with lower survival rates and the clinical stage was shown to be an independent prognostic indicator. A total of 25 cases harbored mutations in c-kit exon 11. The frequency of c-kit mutation was 32% and 22.5% for gastric and small intestinal GIST, respectively. In gastric GIST, the mutated c-kit was predominant in patients older than 50 years of age. But in the small intestinal GIST, the mutated c-kit was predominant in the age group of 40–49 years. In conclusion, for gastric GIST, clinical stage, tumor size, mitotic index, and risk grade are the prognostic indicators. For small intestinal GIST, necrosis and clinical stage are the prognostic indicators. Small intestinal GIST are more aggressive than gastric GIST. The occurrence of c-kit mutation may correlate with the age of patients.

References

1. Hirota S Isozaki K Moriyama Y Hashimoto K Nishida T Ishiguro S Kawano K Hanada M Kurata A Takeda M Muhammad Tunio G Matsuzawa Y Kanakura Y Shinomura Y Kitamura Y Gain-of-functionmutations of c-kit in human gastrointestinalstromal tumorsScience 1998 279(5350)577580
2. Heinrich M C Corless C L Duensing A McGreevey L Chen C J Joseph N Singer S Griffith DJ Haley A Town A Demetri G D Fletcher C D Fletcher J A PDGFRA acting mutations in gastrointestinalstromal tumorsScience 2003 299(5607)708710
3. Tran T Davila J A El-Serag H B The epidemiology of malignant gastrointestinal stromaltumors: an analysis of 1,458 cases from 1992 to 2000Am J Gastroenterol 2005 100(1)162168
4. Blay J Y Bonvalot S Casali P Choi H Debiec-Richter M Dei Tos A P Emile J F Gronchi A Hogendoorn P C Joensuu H Le Cesne A McClure J Maurel J Nupponen N Ray-Coquard I Reichardt P Sciot R Stroobants S van Glabbeke M van Oosterom A Demetri G D GIST consensus meeting panelists. Consensus meeting forthe management of gastrointestinal stromal tumors. Report of the GISTConsensus Conference of 20–21 March 2004, under the auspicesof ESMO. Ann Oncol 2005 16(4)566578
5. Miettinen M Virolainen M Maarit-Sarlomo-Rikala Gastrointestinal stromal tumors-value ofCD34 antigen in their identification and separation from true leiomyomasand schwannomasAm J Surg Pathol 1995 19(2)207216
6. Fletcher C D Berman J J Corless C Gorstein F Lasota J Longley B J Miettinen M O'Leary T J Remotti H Rubin B P Shmookler B Sobin L H Weiss S W Diagnosis of gastrointestinal stromal tumors: A consensusapproachHum Pathol 2002 33(5)459465
7. Emory T S Sobin L H Lukes L Lee D H O'Leary T J Prognosis of gastrointestinal smooth-muscle(stromal) tumors: dependence on anatomic siteAm J Surg Pathol 1999 23(1)8287
8. Miettinen M Sobin L H Lasota J Gastrointestinal stromal tumors of the stomach: a clinicopathologic,immunohistochemical, and molecular genetic study of 1765 cases withlong-term follow-upAm J Surg Pathol 2005 29(1)5268
9. Miettinen M Makhlouf H Sobin L H Lasota J Gastrointestinalstromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical,and molecular genetic study of 906 cases before imatinib with long-termfollow-upAm J Surg Pathol 2006 30(4)477489
10. Changchien C R Wu M C Tasi W S Tang R Chiang J M Chen J S Huang S F Wang J Y Yeh C Y Evaluationof prognosis for malignant rectal gastrointestinal stromal tumor byclinical parameters and immunohistochemical stainingDis Colon Rectum 2004 47(11)19221929
11. Ozgüç H Yilmazlar T Yerci O Soylu R Tümay V Filiz G Zorluoglu A Analysis of prognostic andimmunohistochemical factors in gastrointestinal stromal tumors withmalignant potentialJ Gastrointest Surg 2005 9(3)418429
12. Cheng Y H Yang G H Guo L X Gastrointestinal stromal tumors: A pathomorphologic andimmunohistochemical study of 77 casesLinChuang Yu Shi Yan Bing Li Xue Za Zhi 2001 17(2)123127(in Chinese)
13. Zhao H L Li H F Wang S Q Su A G Liu X P You L B Gastrointestinalstromal tumors: a clinicopathologic and immunohistochemical studyof 162 casesZhonghua Zhong Liu Xue Za Zhi 1998 4(4)313315(in Chinese)
14. Bai Y K Sao Y F Shi S S Gao Y N Sun Y T Cheng S J Liu X Y Gastrointestinal stromal tumors:a multivariate prognostic analysisZhonghuaZhong Liu Xue Za Zhi 2005 127(10)598601 (in Chinese)
15. Heinrich M C Corless C L Demetri G D Blanke C D von Mehren M Joensuu H McGreevey L S Chen C J Van den Abbeele A D Druker B J Kiese B Eisenberg B Roberts P J Singer S Fletcher C D Silberman S Dimitrijevic S Fletcher J A Kinase mutations and imatinibresponse in patients with metastatic gastrointestinal stromal tumorJ Clin Oncol 2003 21(23)43424349
16. Kim T W Lee H Kang Y K Choe M S Ryu M H Chang H M Kim J S Yook J H Kim B S Lee J S Prognostic significance of c-kit mutationin localized gastrointestinal stromal tumorsClin Cancer Res 2004 10(9)30763081
17. Lasota J Jasinski M Sarlomo-Rikala M Miettinen M Mutationsin Exon 11 of c-Kit Occur Preferentially in Malignant versus BenignGastrointestinal Stromal Tumors and Do Not Occur in Leiomyomas orLeiomyosarcomasAm J Pathol 1999 154(1)5360
18. Singer S Rubin B P Lux M L Chen C J Demetri G D Fletcher C D Fletcher J A Prognostic value of KIT mutationtype, mitotic activity, and histologic subtype in gastrointestinalstromal tumorsJ Clin Oncol 2002 20(18)38983905
19. Rutkowski P Nowecki Z I Michej W Debiec-Rychter M Woźniak A Limon J Siedlecki J Grzesiakowska U Kakol M Osuch C Polkowski M Głuszek S Zurawski Z Ruka W Risk criteria and prognostic factors for predicting recurrencesafter resection of primary gastrointestinal stromal tumorAnn Surg Oncol 2007 14(7)20182027
20. Wardelmann E Losen I Hans V Neidt I Speidel N Bierhoff E Heinicke T Pietsch T Büttner R Merkelbach-Bruse S Deletion of Trp-557 and Lys-558in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinalstromal tumors Int J Cancer 2003 106(6)887895
21. Martín J Poveda A Llombart-Bosch A Ramos R López-Guerrero J A García del Muro J Maurel J Calabuig S Gutierrez A Gonzálezde Sande J L Martínez J De Juan A Laínez N Losa F Alija V Escudero P Casado A García P Blanco R Buesa J M Spanish Group for Sarcoma Research. Deletionsaffecting codons 557–558 of the c-kit gene indicate a poor prognosis in patients with completely resectedgastrointestinal stromal tumors: a study by the Spanish group forsarcoma research (GEIS)J Clin Oncol 2005 23(25)61906198
22. Antonescu C R Sommer G Sarran L Tschernyavsky S J Riedel E Woodruff J M Robson M Maki R Brennan M F Ladanyi M DeMatteo R P Besmer P Association ofKIT exon 9 mutations with non-gastric primary site and aggressivebehavior: KIT mutation analysis and clinical correlates of 120 gastrointestinalstromal tumorsClin Cancer Res 2003 9(9)33293337
23. Lasota J Kopczynski J Sarlomo-Rikala M Schneider-Stock R Stachura T Kordek R Michal M Boltze C Roessner A Stachura J Miettinen M KIT 1530ins6 mutation defines a subset of predominantlymalignant gastrointestinal stromal tumors of intestinal originHum Pathol 2003 34(12)13061312