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세아 야
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1 Continuing Education Column Clinical Practice Guideline for Adequate Diagnosis and Effective Treatment of Gastrointestinal Stromal Tumor in Korea Korean Gastrointestinal Stromal Tumor Study Group Yoon Koo Kang, MD Devision of Oncology / Department of Internal Medicine, Ulsan University College of Medicine E mail : ykkang@amc.seoul.kr J Korean Med Assoc 2007; 50(9): Abstract Despite the rarity in incidence and prevalence, gastrointestinal stromal tumor (GIST) has emerged as a distinct pathogenetic entity, and the clinical management of GIST has been evolving very rapidly due to the recent recognition of its oncogenic signal transduction pathway and the introduction of new molecular targeted therapy. Successful management of GIST in localized and advanced stages requires a multidisciplinary approach firmly based on accurate histopathologic diagnosis. However, standardized guidelines for the management of Korean GIST patients do not exist. This study was performed to provide a guideline for standardized diagnosis and treatment for GIST in Korea. Expert panel members of the Korean GIST Study Group (KGSG) thoroughly reviewed the relevant literature including European Society of Medical Oncology and National Comprehensive Cancer Network guidelines and shared their experience and opinions to make a consensus on twenty five topics related with pathologic diagnosis, surgical management, and medical treatment of GIST. The consensus described in this article was presented as the basis for a guideline of diagnosis and treatment for patients with GIST that would be used to facilitate the optimal clinical practice in Korea. Keywords : Guideline; GIST; Diagnosis; Surgery; Imatinib; Sunitinib 830

kr J Korean Med Assoc 2007; 50(9): 830-841 Abstract Despite the rarity in incidence and prevalence, gastrointestinal stromal tumor (GIST) has emerged as a distinct pathogenetic entity, and the

2 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea A B C D E F Figure 1. Photograph of the representative findings of gastrointestinal stromal tumors (GISTs). A) Epithelioid type GIST. B) Spindle cell type GIST. C) Mixed epithelioid and spindle cell type GIST. D) Hyaline changes observed in GIST. E) Myxoid changes observed in GIST. F) Ischemic tumor necrosis observed in GIST. 831

A) Epithelioid type GIST. B) Spindle cell type GIST.

3 Korean GIST Study Group A B C D Figure 2. Immunohistochemical staining of c kit in gastrointestinal stromal tumor. c kit is diffusely positive in the cytoplasm and membranes (A&B). In this picture, internal negative control is vascular endothelial cells. Sometimes, c kit is more intensely stained along the membrane (C). Less frequently, perinuclear golgi like staining can be observed (D). 832

c kit is diffusely positive in the cytoplasm and membranes (A&B).

4 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea 833

5 Korean GIST Study Group Table 1. Proposed approach for defining risk of aggressive behavior in GISTs Size Mitotic Count Very low risk 2 cm 5 / 50 HPF Low risk 2 ~ 5 cm 5 / 50 HPF Intermediate risk 5 cm 6~10 / 50 HPF 5~ 10 cm 5 / 50 HPF High risk 5 cm 5 / 50 HPF 10 cm Any mitotic rate Any size 10 / 50 HPF Abbreviation: HPF, high power field. Table 2. Risk stratification of primary GISTs* Tumor features Risk of tumor progression Mitotic index Size (cm) Stomach Small bowel 5 / 50 HPF 2 Very low Very low 2 and 5 Very low Low 5 and 10 Low Moderate 10 Moderate High 5 / 50 HPF 2 Very low Moderate 2 and 5 Moderate High 5 and 10 High High 10 High High * GISTs arising at other anatomical sites should probably be stratified in a similar fashion as small bowel tumors 834

5 / 50 HPF High risk 5 cm 5 / 50 HPF 10 cm Any mitotic rate Any size 10 / 50 HPF Abbreviation: HPF, high power field. Table 2.

6 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea Figure 3. Algorithm to diagnose gastrointestinal stromal tumors based on immunohistochemistry. 835

7 Korean GIST Study Group 836

8 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea 837

9 Korean GIST Study Group 838

10 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea 11. 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: Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH, Jeong JS, Cho MY, Jin SY, Choi JS, Kang DY. Gastrointestinal stromal tumors in Koreans: It's incidence and the clinical, pathologic and immunohistochemical findings. J Korean Med Sci 2005; 20: Miettinen M, Lasota J. Gastrointestinal stromal tumors: Review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006; 130: Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH, Jeong JS, Cho MY, Jin SY, Choi JS, Kang DY. PKC theta expression in gastrointestinal stromal tumor. Mod Pathol 2006; 19: Miettinen MM, Sarlomo Rikala M, Kovatich AJ, Lasota J. Calponin and h caldesmon in soft tissue tumors: Consistent h caldesmon immunoreactivity in gastrointestinal stromal tumors indicates traits of smooth muscle differentiation. Mod Pathol 1999; 12: Hornick JL, Fletcher CD. The role of KIT in the management of patients with gastrointestinal stromal tumors. Hum Pathol 2007; 38: Townsend. CM, ed. Sabiston textbook of surgery: The biological basis of modern surgical practice, 17th ed. Philadelphia, W.B. Saunders Co., Brunicardi FC, ed. Schwartz's principles of surgery, 8th ed. New York: McGraw Hill, Medical Publishing Division, Trent JC, Benjamin RS. New developments in gastrointestinal stromal tumor. Curr Opin Oncol 2006;18: Blay JY, Bonvalot S, Casali P, Choi H, Debiec Richter M, Dei Tos AP, Emile JF, Gronchi A, Hogendoorn PCW, Joensuu H, Le Cesne A, Mac Clure J, Maurel J, Nupponen N, Ray Coquard I, Reichardt P, Sciot R, Stroobants S, van Glabbeke M, van Oosterom A, Demetri GD. Consensus meeting for the management of gastrointestinal stromal tumors: Report of the GIST consensus conference of March 2004, under the 839

A consensus approach. Hum Pathol 2002; 33: 459-465. 12. Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH, Jeong JS, Cho MY, Jin SY, Choi JS, Kang DY.

11 Korean GIST Study Group auspices of ESMO. Ann Oncol 2005; 16: Gold JS, Dematteo RP. Combined surgical and molecular therapy: The gastrointestinal stromal tumor model. Ann Surg 2006; 244: Iwahashi M, Takifuji K, Ojima T, Nakamura M, Nakamori M, Nakatani Y, Ueda K, Ishida K, Naka T, Ono K, Yamaue H. Surgical management of small gastrointestinal stromal tumors of the stomach. World J Surg 2006; 30: Otani Y, Furukawa T, Yoshida M, Saikawa Y, Wada N, Ueda M, Kubota T, Mukai M, Kameyama K, Sugino Y, Kumai K, Kitajima M. Operative indications for relatively small (2~5cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 2006; 139: Choi SM, Kim MC, Jung GJ, Kim HH, Kwon HC, Choi SR, Jang JS, Jeong JS. Laparoscopic wedge resection for gastric GIST; long term follow up results. Eur J Surg Oncol 2007; 33: Novitsky YW, Kercher KW, Sing RF, Heniford BT. Long term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 2006; 243: ; discussion DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, Fletcher CD, Demetri GD, Bertagnolli MM. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24: DeMatteo RP, Owzar K, Maki RG, Pisters PW, Blackstein M, Antonescu CR, Blanke C, Demetri G, Von Mehren M, Ballman K, and the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvnat GIST Study Team. Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Iintergroup phase III trial ACOSGO Z9001. J Clin Oncol (Meeting Abstracts) 2007; 25: abstr Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, Kim JS, Yook JH, Kim BS, Lee JS. Prognostic significance of c KIT mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 2004; 10: Bumming P, Andersson J, Meis Kindblom JM, Klingenstierna H, Engstrom K, Stierner U, Wangberg B, Jansson S, Ahlman H, Kindblom LG, Nilsson B. Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib: A centre based study of 17 patients. Br J Cancer 2003; 89: Loughrey MB, Mitchell C, Mann GB, Michael M, Waring PM. Gastrointestinal stromal tumour treated with neoadjuvant imatinib. J Clin Pathol 2005; 58: Oh JS, Lee J L, Kim M J, Ryu M H, Chang HM, Kim T W, Jansg SJ, Yook JH, Oh ST, Kim BS, Kang YK. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors of the stomach: Report of three cases. Cancer Res Treat 2006; 38: DeMatteo RP, Heinrich MC, El Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: Before and after STI 571. Hum Pathol 2002; 33: Rankin C, Von Mehren M, Blanke C, Benjamin R, Fletcher CDM, Bramwell V, Crowley J, Borden E, Demetri GD. Dose effect of imatinib (im) in patients (pts) with metastatic GIST phase III sarcoma group study S0033. J Clin Oncol (Meeting Abstracts) 2004; 22: Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I. Progression free survival in gastrointestinal stromal tumours with high dose imatinib: Randomised trial. Lancet 2004; 364: Debiec Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay J Y, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I. Kit mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42: Lee J L, Ryu M H, Chang HM, Kim TW, Kang HJ, Sohn HJ, Lee JS, Kang Y K. Clinical outcome in gastrointestinal stromal tumor patients who interrupted imatinib after achieving stable disease or better response. Jpn J Clin Oncol 2006; 36: Blay J Y, Le Cesne A, Ray Coquard I, Bui B, Duffaud F, Delbaldo C, Adenis A, Viens P, Rios M, Bompas E, Cupissol D, Guillemet C, Kerbrat P, Fayette J, Chabaud S, Berthaud P, Perol D. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French Sarcoma Group. J Clin Oncol 2007; 25: Ryu M H, Lee J L, Chang HM, Kim TW, Kang HJ, Sohn HJ, S. LJ, Kang Y K. Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Jpn J Clin Oncol 2006; 36: Stroobants S, Goeminne J, Seegers M, Dimitrijevic S, Dupont P, Nuyts J, Martens M, van den Borne B, Cole P, Sciot R. 18 FDG positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (glivec ). Eur J Cancer 2003; 39: Jager PL, Gietema JA, van der Graaf WT. Imatinib mesylate 840

Surgical management of small gastrointestinal stromal tumors of the stomach. World J Surg 2006; 30: 28-35. 13.

12 Diagnosis and Treatment of Gastrointestinal Stromal Tumor in Korea for the treatment of gastrointestinal stromal tumours: Best monitored with FDG PET. Nucl Med Commun 2004; 25: Antoch G, Kanja J, Bauer S, Kuehl H, Renzing Koehler K, Schuette J, Bockisch A, Debatin JF, Freudenberg LS. Comparison of PET, CT, and dual modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004; 45: Linton KM, Taylor MB, Radford JA. Response evaluation in gastrointestinal stromal tumours treated with imatinib: Misdiagnosis of disease progression on CT due to cystic change in liver metastases. Br J Radiol 2006; 79: e Choi H, Charnsangavej C, Faria SdC, Tamm EP, Benjamin RS, Johnson MM, Macapinlac HA, Podoloff DA. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: A quantitative analysis correlated with FDG PET findings. Am J Roentgenol 2004; 183: Desai J, Shankar S, Heinrich MC, Fletcher JA, Fletcher CDM, Tuncali K, Silverman SG, Van den Abbeele AD, VanSonnenberg E, Demetri GD. Clonal evolution of resistance to imatinib (im) in patients (pts) with gastrointestinal stromal tumor (GIST): Molecular and radiologic evaluation of new lesions. J Clin Oncol (Meeting Abstracts) 2004; 23: 197(abstr 3010). 36. Bauer S, Hart J, de Wit M, Lang H, Grabellus F, Antoch G, Niebel W, Erhard J, Ebeling P, Zeth M, Taeger G, Seeber S, Flasshove M, Schutte J. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer 2005; 117: Dileo P, Randhawa R, Vansonnenberg E, Shankar S, Desai J, Morgan JA, Tuncali K, Van Den Abbeele A, Silverman SG, Demetri GD. Safety and efficacy of percutaneous radio frequency ablation (RFA) in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) with clonal evolution of lesions refractory to imatinib mesylate (im). J Clin Oncol (Meeting Abstracts) 2004; 22: Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR. Outcome of patients with advanced gastro intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400mg. Eur J Cancer 2005; 41: Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006; 368: Peer Reviewer Commentary 841

Comparison of PET, CT, and dual modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004; 45: 357-365. 33.

레이아웃 1

레이아웃 1 대한위장관기질종양연구회 01 GIST 06 02 11 03 Imatinib 14 04 05 06 07 Sunitinib 32 40 44 48 GIST 6 01 7 GIST Guide book GIST 8 01 9 GIST Guide book GIST (CT) MRI FDG-PET 10 02 11 GIST Guide book 12 02 (Imatinib)