期刊论文详细信息
World Journal of Surgical Oncology
Prognostic impact of gastrointestinal bleeding and expression of PTEN and Ki-67 on primary gastrointestinal stromal tumors
Liang Zong1  Hai-Hang Zhu3  Chang-Ren Zhu4  Xue-Wen Gu4  Lei Shi2  Wei Zhao2  Xin-Xin Liu2  Ping Chen2  Hao Wang2 
[1] Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;Department of Gastrointestinal Surgery, Clinical Medical College of Yangzhou University, No. 98, Nan-Tong West Road, Yangzhou, Jiangsu 225001, P.R. China;Department of Gastroenterology, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu Province 225001, P.R. China;Department of Pathology, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu Province 225001, P.R. China
关键词: tissue microarray;    PTEN;    prognosis;    Ki-67 labeling index;    immunohistochemistry;    gastrointestinal stromal tumors;    gastrointestinal bleeding;   
Others  :  819984
DOI  :  10.1186/1477-7819-12-89
 received in 2013-11-22, accepted in 2014-03-30,  发布年份 2014
PDF
【 摘 要 】

Background

Prognostic indicators for gastrointestinal stromal tumors (GISTs) are under investigation. The latest risk classification criteria may still have room for improvement. This study aims to investigate prognostic factors for primary GISTs from three aspects, including clinicopathological parameters, immunohistochemical (IHC) expression of PTEN, and Ki-67 labeling index (LI), and attempts to find valuable predictors for the malignancy potential of primary GISTs.

Methods

Tumor samples and clinicopathological data from 84 patients with primary GISTs after R0 resection were obtained. Immunohistochemical analysis was performed based on tissue microarray (TMA) to estimate expression of PTEN and Ki-67 in tumor cells.

Results

The cut-off point of Ki-67 LI was determined as 1%, using a receiver operator characteristic test with a sensitivity of 71.7% and a specificity of 64.5%. Univariate analysis demonstrated the following factors as poor prognostic indicators for relapse-free survival (RFS) against a median follow-up of 40.25 months: gastrointestinal (GI) bleeding (P = 0.009), non-gastric tumor location (P = 0.001), large tumor size (P = 0.022), high mitotic index (P < 0.001), high cellularity (P = 0.012), tumor rupture (P = 0.013), absent or low expression of PTEN (P = 0.036), and Ki-67 LI >1% (P = 0.043). Gastrointestinal bleeding (hazard ratio, 3.85; 95% confidence interval, 1.63 to 9.10; P = 0.002) was a negative independent risk predictor in multivariate analysis, in addition to tumor size (P = 0.023), and mitotic index (P = 0.002). In addition, GI bleeding showed a good ability to predict recurrence potential, when included in our re-modified risk stratification criteria.

Conclusions

This study suggests that GI bleeding is an independent predictor of poor prognosis for RFS in primary GISTs. Expression of PTEN and Ki-67 are correlated with high risk potential and may predict early recurrence in univariate analysis.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140712021336675.pdf 1065KB PDF download
Figure 2. 65KB Image download
Figure 1. 189KB Image download
【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】
  • [1]Steigen SE, Eide TJ: Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of northern Norway. APMIS 2006, 114(3):192-200.
  • [2]Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, Sablinska K, Kindblom LG: Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era: a population-based study in western Sweden. Cancer 2005, 103(4):821-829.
  • [3]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-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998, 279(5350):577-580.
  • [4]Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003, 299(5607):708-710.
  • [5]Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW: Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002, 33(5):459-465.
  • [6]Miettinen M, Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006, 23(2):70-83.
  • [7]Joensuu H: Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008, 39(10):1411-1419.
  • [8]Di Cristofano A, Pandolfi PP: The multiple roles of PTEN in tumor suppression. Cell 2000, 100(4):387-390.
  • [9]Bauer S, Duensing A, Demetri GD, Fletcher JA: KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 2007, 26(54):7560-7568.
  • [10]Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R: Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999, 96(4):1563-1568.
  • [11]Waite KA, Eng C: Protean PTEN: form and function. Am J Hum Genet 2002, 70(4):829-844.
  • [12]Chalhoub N, Baker SJ: PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009, 4:127-150.
  • [13]Weigel MT, Dowsett M: Current and emerging biomarkers in breast cancer: prognosis and prediction. Endocr Relat Cancer 2010, 17(4):R245-R262.
  • [14]Seidal T, Edvardsson H: Expression of c-kit (CD117) and Ki67 provides information about the possible cell of origin and clinical course of gastrointestinal stromal tumours. Histopathology 1999, 34(5):416-424.
  • [15]Wong NA, Young R, Malcomson RD, Nayar AG, Jamieson LA, Save VE, Carey FA, Brewster DH, Han C, Al-Nafussi A: Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach. Histopathology 2003, 43(2):118-126.
  • [16]Miettinen M, Lasota J: Gastrointestinal stromal tumors. Gastroenterol Clin North Am 2013, 42(2):399-415.
  • [17]Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005, 29(1):52-68.
  • [18]Trupiano JK, Stewart RE, Misick C, Appelman HD, Goldblum JR: Gastric stromal tumors: a clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive behaviors. Am J Surg Pathol 2002, 26(6):705-714.
  • [19]Lv A, Li Z, Tian X, Guan X, Zhao M, Dong B, Hao C: SKP2 high expression, KIT Exon 11 deletions, and gastrointestinal bleeding as predictors of poor prognosis in primary gastrointestinal stromal tumors. PLoS One 2013, 8(5):e62951.
  • [20]Deneubourg L, Ralea S, Gromova P, Parsons R, Vanderwinden JM, Erneux C: Abnormal elevated PTEN expression in the mouse antrum of a model of GIST Kit (K641E/K641E). Cell Signal 2011, 23(11):1857-1868.
  • [21]Floris G, Wozniak A, Sciot R, Li H, Friedman L, Van Looy T, Wellens J, Vermaelen P, Deroose CM, Fletcher JA, Debiec-Rychter M, Schöffski P: A potent combination of the novel PI3K inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal. Clin Cancer Res 2013, 19(3):620-630.
  • [22]Ricci R, Maggiano N, Castri F, Rinelli A, Murazio M, Pacelli F, Potenza AE, Vecchio FM, Larocca LM: Role of PTEN in gastrointestinal stromal tumor progression. Arch Pathol Lab Med 2004, 128(4):421-425.
  • [23]Liang YM, Li XH, Li WM, Lu YY: Prognostic significance of PTEN, Ki-67 and CD44s expression patterns in gastrointestinal stromal tumors. World J Gastroenterol 2012, 18(14):1664-1671.
  • [24]Tachibana M, Shibakita M, Ohno S, Kinugasa S, Yoshimura H, Ueda S, Fujii T, Rahman MA, Dhar DK, Nagasue N: Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma. Cancer 2002, 94(7):1955-1960.
  • [25]Ozgüç H, Yilmazlar T, Yerci O, Soylu R, Tümay V, Filiz G, Zorluoglu A: Analysis of prognostic and immunohistochemical factors in gastrointestinal stromal tumors with malignant potential. J Gastrointest Surg 2005, 9(3):418-429.
  • [26]Bertolini V, Chiaravalli AM, Klersy C, Placidi C, Marchet S, Boni L, Capella C: Gastrointestinal stromal tumors - frequency, malignancy, and new prognostic factors: the experience of a single institution. Pathol Res Pract 2008, 204(4):219-233.
  • [27]Cerski MR, Pereira F, Matte US, Oliveira FH, Crusius FL, Waengertner LE, Osvaldt A, Fornari F, Meurer L: Exon 11 mutations, Ki67, and p16 (INK4A) as predictors of prognosis in patients with GIST. Pathol Res Pract 2011, 207(11):701-706.
  • [28]Belev B, Brčić I, Prejac J, Golubić ZA, Vrbanec D, Božikov J, Alerić I, Boban M, Razumović JJ: Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors. World J Gastroenterol 2013, 19(4):523-527.
  • [29]Filiz G, Yalçinkaya O, Gürel S, Yerci O, Memik F: The relationship between MIB-1 proliferative activity and mitotic index in gastrointestinal stromal tumors. Hepatogastroenterology 2007, 54(74):438-441.
  • [30]Joensuu H, Hohenberger P, Corless CL: Gastrointestinal stromal tumour. Lancet 2013, 382(9896):973-983.
  • [31]Nagasako Y, Misawa K, Kohashi S, Hasegawa K, Okawa Y, Sano H, Takada A, Sato H: Evaluation of malignancy using Ki-67 labeling index for gastric stromal tumor. Gastric Cancer 2003, 6(3):168-172.
  • [32]Molenaar WM, Plaat BE, Berends ER, te Meerman GJ: Observer reliability in assessment of mitotic activity and MIB-1-determined proliferation rate in pediatric sarcomas. Ann Diagn Pathol 2000, 4(4):228-235.
  • [33]Joensuu H, Vehtari A, Riihimäki J, Nishida T, Steigen SE, Brabec P, Plank L, Nilsson B, Cirilli C, Braconi C, Bordoni A, Magnusson MK, Linke Z, Sufliarsky J, Federico M, Jonasson JG, Dei Tos AP, Rutkowski P: Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012, 13(3):265-274.
  • [34]Hohenberger P, Ronellenfitsch U, Oladeji O, Pink D, Ströbel P, Wardelmann E, Reichardt P: Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg 2010, 97(12):1854-1859.
  • [35]Dematteo RP, Gold JS, Saran L, Gönen M, Liau KH, Maki RG, Singer S, Besmer P, Brennan MF, Antonescu CR: Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008, 112(3):608-615.
  • [36]Bubendorf L, Nocito A, Moch H, Sauter G: Tissue microarray (TMA) technology: miniaturized pathology archives for high–throughput in situ studies. J Pathol 2001, 195(1):72-79.
  文献评价指标  
  下载次数:8次 浏览次数:26次