DOG1 Antibody in the Differential Diagnosis of Gastrointestinal Stromal Tumors

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, 6825 16th Street, NW, Building 54, Room G090,Washington, DC 20306-6000, USA.
The American journal of surgical pathology (Impact Factor: 5.15). 08/2009; 33(9):1401-8. DOI: 10.1097/PAS.0b013e3181a90e1a
Source: PubMed


Gastrointestinal stromal tumors (GISTs), KIT or platelet derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors of the gastrointestinal (GI)-tract and abdomen, require a precise diagnosis so that the patients may benefit from the newly introduced tyrosine kinase inhibitor drugs. The limitations of the current main tools, KIT immunohistochemistry and KIT/PDGFRA mutation analysis, include lack of KIT expression and mutations in some GISTs. In this study we examined 1168 GISTs of different sites and histologic subtypes, and 672 other tumors and normal tissues for discovered on GIST-1 (DOG1) clone K9, a newly introduced immunohistochemical marker, a chloride channel protein. All GISTs and selected non-GISTs were independently evaluated for KIT. In the GI tract, Cajal cells and gastric surface epithelia were DOG1-positive. The overall sensitivity of DOG1 and KIT in GISTs was nearly identical: 94.4% and 94.7%, and results in GISTs were generally concordant. Gastric spindle cell GISTs was nearly uniformly positive for both markers, whereas DOG1 performed slightly better in gastric epithelioid GISTs that included PDGFRA mutant GISTs. In the intestinal GISTs, KIT was slightly more sensitive than DOG1. Negativity for both DOG1 and KIT was observed in 2.6% of GISTs of GI tract. KIT or PDGFRA mutations were detected in 11/24 DOG1-negative GISTs supporting the diagnosis of GIST. DOG1 expression was also generally present in extragastrointestinal and metastatic GISTs. DOG1 was highly specific for GIST, but exceptional DOG1-positive other mesenchymal tumors included uterine type retroperitoneal leiomyomas, peritoneal leiomyomatosis, and synovial sarcomas (positive in 5/42, 4/17, and 6/37 cases). Leiomyomas colonized by DOG1-positive Cajal cells should not be confused with GISTs. DOG1 positivity was relatively common in esophageal squamous cell and gastric carcinomas, whereas it was rare in colorectal carcinomas. DOG1 should be added into the diagnostic panel evaluating GI and other abdominal tumors, but limitations in its sensitivity and specificity should be recognized.

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    • "However, it warrants further investigation into possible disease related risk differences in future studies. Obviously, the advancement in diagnostic assessment as well as outline of mutational subtypes continue to progress[18,21,65,66]. As most of the studies reported in the current collected series predated the current knowledge on mutational status and advancements in molecular classification[67,68], it was not possible to collate such information. "
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    ABSTRACT: Background: Gastrointestinal stromal tumours (GISTs) are rare, yet the most common mesenchymal tumour within the digestive tract. Lack of diagnostic criteria and no specific code in the ICD system has prevented epidemiological evaluation except from overt malignant cases in the past. A global estimate of incidence and disease patterns has thus not been available. Methods: A systematic literature search of all available population-based studies on GIST published between January 2000 and December 2014 were reviewed. Descriptive epidemiological data are presented. Results: The search found 29 studies of more than 13,550 patients from 19 countries that reported sufficient data for regional or national population-based statistics. Age at diagnosis ranged from 10 to 100 years, with median age being mid 60s across most studies. Gender distribution was equal across studies. On average, 18% of patients had an incidental diagnosis (range from 5% to 40%). Anatomical location of primary tumour in 9747 GISTs demonstrated gastric location as the most frequent (55.6%) followed by small bowel (31.8%), colorectal (6.0%), other/various location (5.5%) and oesophagus (0.7%). Most studies reported incidence at 10-15 per million per year. Notably, lowest incidence was in China (Shanxi province) with 4.3 per million per year. Highest incidence rates were reported also from China (Hong Kong and Shanghai areas), and in Taiwan and Norway (Northern part), with up to 19-22 per million per year. Conclusions: Epidemiology of GIST demonstrates some consistent features across geographical regions. Whether the reported extreme differences in incidence reflect real variation in population risk warrants further investigation.
    Full-text · Article · Feb 2016
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    • "An attempt has been made to define the most specific immunohistochemical panel for the diagnostic algorithm by comparing the expression rates with CD117 in almost all studies with DOG1 in the literature. The rate of DOG1 positivity was 20-100% in CD117 negative GIST cases in different studies, all of which reported that DOG1 should be added to the immunohistochemical panel in the diagnostic steps independent of the mutation status (2,67829,31,38,42). In the present study, positivity with CD117 was provided by applying the immunohistochemical studies on multiple different paraffin blocks in those cases which could be negative for CD117 (focally and weak reaction). "
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    ABSTRACT: Background: Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor α (PDGFRα) mutations affecting receptor tyrosine kinase activity and do not benefit from classic treatment regimens. Aims: The aim of this study was to review the algorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression characteristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression. Study Design: Diagnostic accuracy study. Methods: We reevaluated the histological and immunohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diagnosis panel antibodies (CD117, PDGFRα, CD34, vimentin, 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 PDGFRα immune marker for which the benefit in routine practice is discussed. Results: Classification according to progressive disease 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<0.05). Positive immunoreaction was observed with CD117 and PDGFRα in all GISTs in the study (100%). Positivity with the DOG1 antibody was found in 33 (89%) cases. CD34 was positive in 62% (23) of the cases. Conclusion: The CD117 antibody still plays a key role in GIST diagnosis. However, the use of DOG1 and PDGFRα antibodies combined with CD117 as sensitive markers can be beneficial.
    Full-text · Article · Oct 2015 · Balkan Medical Journal
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    • "DOG1 also known as TMEM16A or ANO1 is a calcium-dependent, receptoractivated chloride channel protein and seems to be expressed in GIST independently of the type of mutation [30]. In a study of 1168 cases of GISTs, the overall sensitivity of DOG1 and KIT was nearly identical (94.4% and 94.7%, respectively) and a high concordance was found between DOG1 and KIT immunohistochemistry (92.3% positivity for both) [31]. RNA-Binding protein with multiple splicing 2 (RBPMS2), an early marker of gastrointestinal SMC embryonic precursors, was significantly highly expressed in GIST samples, particularly in high risk tumours compared to control gastrointestinal tissues [32]. "

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