DOG1 Expression in Soft Tissue Tumors

Dear Editor: DOG1 (discovered on GIST-1; ANO1) was identified from gene expression profiling studies on gastrointestinal stromal tumor (GIST). It is a membrane-bound ion channel highly expressed by interstitial cells of Cajal, and which is important for their function. DOG1 immunohistochemistry has been noted for its high sensitivity and specificity for GIST, with expression in >98% and with higher sensitivity than KIT, including in unusual subtypes such as PDGFRA-mutant and KIT-negative and SDHB-D-mutant and SDHA-mutant tumors, and in metastatic and extragastrointestinal cases. Expression is typically diffuse and strong within the cytoplasm and membrane. We recently demonstrated that DOG1 was expressed in half of molecularly confirmed low-grade fibromyxoid sarcomas (LGFMS), showing a range of intensities and distributions, including strong, diffuse, or multifocal cytoplasmic and membranous expression. Diffuse expression was present within the index case, a pelvic/pararectal LGFMS initially considered to represent GIST. DOG1 positivity can be a particular diagnostic pitfall in intraabdominal/intrapelvic LGFMS, as these are rare, may be less likely anticipated at these sites, can show a morphologic spectrum that may overlap with GIST, and may not be fully represented on core biopsy. DOG1 expression is increasingly recognized in other mesenchymal tumors, including potential GIST mimics. Variable positivity has been shown in soft tissue glomus tumors, small numbers of benign and malignant smooth muscle neoplasms, Ewing sarcomas, schwannomas, malignant peripheral nerve sheath tumors, and synovial sarcomas, although expression is often weak and focal. A recent study of 4 intraabdominal synovial sarcomas harboring SS18 gene rearrangement showed DOG1 positivity in all. In view of finding DOG1 expression in a proportion of LGFMS, we prospectively assessed DOG1 immunohistochemistry (with DOG1 antibody [clone K9; Leica, Novocastra Laboratories, Newcastle upon Tyne, UK; 1:50]) in 100 further non-GIST soft tissue neoplasms. All cases were formalin-fixed and paraffin-embedded and comprised consecutive biopsies or excision specimens. Of these, only 5 showed expression of DOG1 (Table 1), comprising one each of myxofibrosarcoma (strong expression in 10% of cells), nodular fasciitis (moderate in 15%), undifferentiated pleomorphic sarcoma, synovial sarcoma, and myxoid liposarcoma (moderate in 20%, 5%, and 5% respectively). Expression in each was membranous and cytoplasmic (Figure 1). The remaining 95 cases showed no DOG1 expression. Further to our previous study, which showed that LGFMS had variable DOG1 expression in 5% to 75% of cells, we demonstrate here that moderate to strong DOG1 expression occurs in a small number of other soft tissue tumors. Of note, expression was only focal, and not the diffuse positivity typical of GIST. In addition, of these, only synovial sarcoma would realistically enter the morphological differential diagnosis of GIST; this is a particular pitfall in intraabdominal cases, because these may coexpress CD117, and the therapeutic options are different. We emphasize that DOG1 remains a highly useful marker for GIST, but that the surgical pathologist needs to be aware of the potential pitfall of its occasional expression in mesenchymal tumors that may enter its differential diagnosis (particularly intraabdominal/pelvic LGFMS and synovial sarcoma). Extra vigilance is required with biopsy material, which may not represent the complete tumor morphology. 621967 IJSXXX10.1177/1066896915621967International Journal of Surgical PathologyNg et al research-article2015