Burcu TOKUÇ, Filiz ÖZYILMAZ, Nuray CAN, Ebru TAŞTEKİN, Beril GÜLER

Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis

Background: Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor ? (PDGFR?) mutations affecting receptor tyrosine ki-nase activity and do not benefit from classic treatment regimens.Aims: The aim of this study was to review the al-gorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression charac-teristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression.Study Design: Diagnostic accuracy study.Methods: We reevaluated the histological and immu-nohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diag-nosis panel antibodies (CD117, PDGFR?, CD34, vi-mentin, desmin, SMA, S-100, and Ki67) were studied on the tumor sections. We also used the popular marker DOG1 antibody with accepted sensitivity for GISTs in recent years and the PDGFR? immune marker for which the benefit in routine practice is discussed.Results: Classification according to progressive dis-ease risk groups of the 37 cases revealed that 54% were in the high risk, 19% in the moderate risk, 16% in the low risk, 8% in the very low risk and 8% in the no risk group.Cytological atypia, necrosis, mucosal invasion and the Ki67 index were found to be related to the progressive disease risk groups of the tumors (p

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Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on mor- phology, molecular pathology, prognosis, and differential diagnosis [re- view]. Arch Pathol Lab Med 2006;130:1466-78.
Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol 2009;33:1401-8.
Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgom- ery K, et al. A novel monoclonal antibody against DOG1 is a sensi- tive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 2008;32:210-8.
West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgom- ery K, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors ırrespective of KIT or PDGFRA muta- tion status. Am J Pathol 2004;165:107-13.
Ardeleanu C, Arsene D, Hinescu M, Andrei F, Gutu D, Luca L, et al. Pancreatic expression of DOG1 A novel gastrointestinal stromal tumor (GIST) biomarker. Appl Immunohistochem Mol Morphol 2009;17:413-8.
Liegl B, Hornick JL, Corless CL, Fletcher CD. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastroin- testinal stromal tumors, including unusual subtypes. Am J Surg Pathol
Lopes LF, West RB, Bacchi LM, van de Rijn M, Bacchi CE. DOG1 for the diagnosis of gastrointestinal stromal tumor (GIST): Comparison between 2 different antibodies. Appl Immunohistochem Mol Morphol 2010;18:333-7.
Novelli R, Rossi S, Rodriguez-Justo M, Taniere P, Seddon B, Toffolatti L, et al. DOG1and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology 2010;57:259-70.
Miwa S, Nakajima T, Murai Y, Takano Y, Sugiyama T. Mutation assay of the novel gene DOG1 in gastrointestinal stromal tumors (GISTs). J Gastroenterol 2008;43:531-7.
Lee CH, Liang CW, Espinosa I. The utility of discovered on gastro- intestinal stromal tumor 1 (DOG1) antibody in surgical pathology-the GIST of it [review]. Adv Anat Pathol 2010;17:222-32.
Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Gan- joo KN, Maki RG, et al. NCCN Task Force Report: Update on the management of patients with Gastrointestinal Stromal Tumors. J Natl Compr Canc Netw 2010;8(Suppl 2):S1-41.
Katoh M, Katoh M. FLJ10261 gene, located within the CCND1- EMS1 locus on human chromosome 11q13, encodes the eight-trans- membrane protein homologous to C12orf3, C11orf25 and FLJ34272 gene products. Int J Oncol 2003;22:1375-81.
Galindo BE, Vacquier VD. Phylogeny of the TMEM16 protein family: some members are overexpressed in cancer. Int J Mol Med 2005;16:919-24.
Carles A, Millon R, Cromer A, Ganguli G, Lemaire F, Young J, et al. Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display. Onco- gene 2006;25:1821-31.
Wong NA. Gastrointestinal stromal tumours-an update for His- topathologists. Histopathology 2011;59:807-21.
Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, et al. TMEM16A, a membrane protein associated with calcium- dependent chloride channel activity. Science 2008;322:590-4.
Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, et al. TMEM16A confers receptor-activated calcium-dependent chlo- ride conductance. Nature 2008;455:1210-5.
Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Long- ley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a con- sensus approach [review]. Hum Pathol 2002;33:459-65.
Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tu- mors of the stomach: a clinicopathologic, immunohistochemi- cal, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52-68.
Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cas- es before imatinib with long-term follow-up. Am J Surg Pathol 2006;30:477-89.
Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors [review]. Virchows Arch 2010;456:111-27.
Steigen SE, Eide TJ. Gastrointestinal stromal tumors (GISTs): a review. APMIS 2009;117:73-86.
Nishida T, Hirota S. Biological and clinical review of stromal tumors in the gastrointestinal tract [review]. Histol Histopathol 2000;15:1293-301.
Joensuu H. Gastrointestinal stromal tumor (GIST) [review]. Ann Oncol 2006;17:280-6.
Doğanavşargil B, Akalın T, Sezak M, Alkanat BM, Kandiloğlu G, Tunçyürek M. Gastrointestinal stromal tümörlerde histopa- tolojik değerlendirme "Ege Üniversitesi Tıp Fakültesi Patoloji Anabilim Dalı'nın 1992-2007 yılları arasındaki deneyimi". Ege Journal of Medicine 2008;47:163-70.
Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stro- mal tumors: recent advances in understanding of their biology. Hum Pathol 1999;30:1213-20.
Hou YY, Lu SH, Zhou Y, Xu JF, Ji Y, Hou J, et al. Predic- tive values of clinical and pathological parameters for malig- nancy of gastrointestinal stromal tumors. Histol Histopathol 2009;24:737-47.
Parfitt JR, Streutker CJ, Riddell RH, Driman DK. Gastrointes- tinal stromal tumors: A contemporary review [review]. Pathol Res Pract 2006;202:837-47.
Jung SH, Suh KS, Kang DY, Kang DW, Kim YB, Kim ES. Ex- pression of DOG1, PDGFRA, and p16 in gastrointestinal stro- mal tumors. Gut Liver 2011;5:171-80.
Sui XL, Wang H, Sun XW. Expression of DOG1, CD117 and PDGFRA in gastrointestinal stromal tumors and correlations with clinicopathology. Asian Pac J Cancer Prev 2012;13:1389-93.
Kara T, Serinsoz E, Arpaci RB, Gubur O, Orekici G, Ata A, et al. Contribution of DOG1 expression to the diagnosis of gastro- intestinal stromal tumors. Pathol Res Pract 2013;209:413-7.
Miettinen M, El-Rifai W, H L Sobin L, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 2002;33:478-83.
Dogusoy Bulbul G. (GIST Working Group Turkish Society of Pathology, Turkey). Gastrointestinal stromal tumors: Recent re- sults of a nationwide database including 1008 cases with histo- pathological and immunophenotypical features. 21st European Congress of Pathology. (Oral Presentation), Istanbul. In Vir- chows Arch 2007;451:161.
Selcukbiricik F, Yalçın S, Tural D, Erdamar S, Demir G, Doğusoy G, et al. Gastrointestinal stromal tumors in Turkey: experiences from 3 centers. Onkologie 2013;36:18-24.
Fujimoto Y, Nakanishi Y, Yoshimura K, Shimoda T. Clinico- pathologic study of primary malignant gastrointestinal stromal tumor of the stomach, with special reference to prognostic fac- tors: analysis of results in 140 surgically resected patients. Gas- tric Cancer 2003;6:39-48.
Wong NA, Young R, Malcomson RD, Nayar AG, Jamieson LA, Save VE, et al. Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemi- cal study of 108 resected cases of the stomach. Histopathology
Blay JY, von Mehren M, Blackstein ME. Perspective on updated treatment guidelines for patients with gastrointestinal stromal tumors [review]. Cancer 2010;26:1-11.
Rios-Moreno MJ, Jaramillo S, Gallardo SP, Vallejo A, Mora M, Garcia-Escudero A, et al. Gastrointestinal stromal tumors (GISTs): CD117, DOG-1, and PKC? expression. Is there any advantage in using several markers? Pathol Res Pract 2012;208:74-81.
Huang H, Liu YX, Zhan ZL, Liang H, Wang P, Ren XB. Differ- ent sites and prognoses of gastrointestinal stromal tumors of the stomach: report of 187 cases. World J Surg 2010;34:1523-33.
Lasota J, Corless CL, Heinrich MC, Debiec-Rychter M, Sciot R, Wardelmann E, et al. Clinicopathologic profile of gastroin- testinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Mod Pathol 2008;21:476-84.
Rubin BP. Gastrointestinal stromal tumours: an update [review]. Histopathology 2006;48:83-96.
Ricci R, Dei Tos AP, Rindi G. GISTogram: a graphic presentation of the growing GIST complexity. Virchows Arch 2013;463:481-7.
Peterson MR, Piao Z, Weidner N, Yi ES. Strong PDGFRA posi- tivity is seen in GISTs but not in other intra-abdominal mesen- chymal tumors: Immunohistochemical and mutational analyses. Appl Immunohistochem Mol Morphol 2006;14:390-6.
Rossi G, Valli R, Bertolini F, Marchioni A, Cavazza A, Muc- ciarini C. PDGFR expression in differential diagnosis between KIT-negative gastrointestinal stromal tumours and other prima- ry soft-tissue tumours of the gastrointestinal tract. Histopathol- ogy 2005;46:522-31.