Expression Of DOG1and CD117in Gastrointestinal Stromal Tumors And Its Clinical Significance

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract (GI). Histologically, GISTs demonstrate considerable morphologic overlap with other spindle cell tumors such as GI leiomyomas and schwannomas. GISTs are refractory to standard chemotherapy and radiation. In1998, Hirota group discovered activating mutations in the KIT receptor tyrosine kinase(RTK) gene in GISTs and demonstrated expression of KIT/CD117protein by immunohistochemistry(IHC). Later, it became clear that most GISTs have activating mutations in KIT or the homologous RTK platelet-derived growth factor receptor alpha(PDGFRA) gene. The term GIST is currently defined as "specific, generally CD117+and KIT or PDGFRA mutation-driven mesenchymal tumors of the gastrointestinal tract with a set of characteristic histologic features. Immunopositivity for KIT/CD117has been the main tool for the verification of GIST. KIT/CD117expression had even been regarded as the gold standard for the diagnosis of GISTs. The use of Tyrosine kinase inhibitors (TKIs) such as imatinib mesylate and sunitinib malate for the treatment of recurrent and/or metastatic GISTs revolutionized the treatment of malignant GISTs, and has showed significant effects in most patients with advanced disease, but these TKIs have some side effects and are also expensive treatments. With the growing effectiveness of TKIs therapies, the accurate diagnosis of GIST has become imperative and even more crucial for proper clinical management. Although KIT/CD117is a reliable immunohistochemical marker for the diagnosis of GIST, numerous studies have shown that approximately5%of GISTs lack KIT/CD117expression by IHC, leaving the diagnosis in question. Genetic sequencing demonstrates that most of these tumours harbor mutations in the PDGFRA gene and occasionally KIT mutations. Furthermore, most of the GISTs lacking KIT/CD117expression still respond to TKIs-based therapies. Gene sequencing is becoming an increasingly important component of GIST diagnosis, but it adds to the time and cost of diagnosis and can’t be carried out in most of the routine pathology practice. Compared with gene sequencing, immunohistochemistry, a much faster and more cost effective method, is preferred by pathologists in the initial diagnosis of GISTs. The GIST-specific diagnostic biomarker whose specificity and sensitivity is superior to KIT/CD117have been pursued by pathologists and researchers in post-CD117era. In2004Van de Rijn and West et al discoved gene FLJ10261and its protein product named DOG1(discovered on GIST-1) were highly expressed in GIST. Recent studies suggested that DOG1have similar or better sensitivity and superior specificity compared with KIT/CD117. The present study observed the morphological features of GISTs and examined the expression of DOG1and CD117in GIST to evaluate the diagnosis value of DOG1. The accurate diagnosis of GIST confirmed by the useful biomarkers will provide a strong basis for rational use of gene targeted therapies.Methods:This study collected a total of152cases surgically resected gastrointestinal and abdominal mesenchymal tumors including123cases of primary GISTs, and15cases of other tumors such as seminoma with high expression for CD117, from the files of the Departments of Pathology at Hangzhou First Hospital. A total specimens were fixed by neutral buffered formalin, paraffin-embedded, hematoxylin-eosin(HE) stained and then reviewed to confirm the diagnoses before immunohistochemistry test. Immunohistochemical study for DOG1, CD117, CD34, SMA, Desmin and S-100was performed by En Vision method on123cases of GISTs and44cases of other neoplasms. The SPSS13.0statistical software for statistical analysis was used.Results:The overall sensitivity of DOG1was slightly better than CD117(98.4%vs96.7%) in GISTs, but there were no statistically significant differences between DOG1and CD117expression in GISTs. Compared with CD117, DOG1showed significantly better sensitivity in epithelioid GISTs (88.9%vs66.7%)(p<0.05), but showed similar sensitivity in spindle cell GISTs and mixed cell GISTs. The specificity of DOG1was significantly better than that of CD117. The combined use of DOG1and CD117could define GIST diagnosis in99.2%cases of GISTs.Conclusions:1. The sensitivity of DOG1in GISTs is similar to that of CD117. Moreover, DOG1expression is not significantly correlated with clinicopathologic parameters including patient gender, anatomic location and aggressive risk of the tumor and so on.2. The specificity of DOG1in GISTs is significantly superior to that of CD117, suggesting that DOG1be of important practical value in GIST diagnosis.3. Compared with CD117, DOG1shows a better sensitivity in detecting epithelioid GISTs. 4. In order to improve the diagnostic level of GISTs, a panel of antibodies including DOG1and CD117should be performed in pathologic diagnosis of spindle cell tumors of gastrointestinal tract.