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Selected Publication:

Argyropoulos, A.
Molecular landscape of gastrointestinal stromal tumors – a retrospective study
Humanmedizin; [ Diplomarbeit ] Medizinische Universitaet Graz; 2022. pp.


Authors Med Uni Graz:
Brcic Iva
Liegl-Atzwanger Bernadette

Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive system and occur preferentially in the elderly patients. They are usually well-circumscribed solitary tumors and show either a spindle-, epithelioid- or mixed- cell morphology. The vast majority of cases express DOG1 and CD117 by immunohistochemistry. GISTs harbor mutations in the tyrosine kinase receptor KIT or in platelet-derived growth factor receptor (PDGFRA) in approximately 90% of cases. Tumors without mutation in KIT or PDGFRA are called in a simplified way “wild-type” GISTs (wt-GISTs) and especially in children and young adults these GISTs can be associated with tumor syndromes. Nevertheless, other mutations in GIST like BRAF, NF1 and others have been reported. Molecular analyses with an expanded molecular panel are important for selecting the adequate treatment for patients suffering from this disease. Methods: In this study clinical, histological, immunohistochemical and molecular data of the 81 patients with GIST were collected and evaluated. In addition, treatment, follow-up, and comorbidities were recorded. The data was compared with the literature. Results: GISTs were located most frequently in the stomach and small intestine and ranged in size from 0.8 cm to 20 cm. Histologically, they showed a spindle cell morphology in 41/81 cases, an epithelioid cell morphology in 13/81 cases, and a mixed morphology in 27/81 cases. Immunohistochemically, 95.8% and 95.2% of the tumors showed a positive immunohistochemical staining with DOG-1 and CD117, respectively. Predominantly, GISTs metastasized to the liver and peritoneum; However, metastases to skin, lymph nodes, lung, ovary, and testis were also observed. In 55/81 tumors mutations in either KIT or PDGFRA were found. In total, 45 mutations were detected in the KIT gene: 33 mutations in exon 11, eight mutations in exon 9, two mutations in exon 13, one mutation in exon 8 and one mutation in exon 17. Furthermore, 10 mutations were observed in the PDGFRA gene, one mutation in exon 12 and one mutation in exon 14. The other eight PDGFRA mutations were found in exon 18 – in six cases the PDGFRA D842V mutation – a known Imatinib resistance mutation was observed. Moreover, there was one case with a mutation in KIT 11 and an additional mutation in PDGFRA12. In addition, there were 2 GISTs that harbored a mutation in NF1 and 5 GIST showed a SDH mutation (three SDHA and two SDHB). In 17 GISTs multiple mutations were detected. No mutations were detected in two tumors: the Archer Fusion Plex Sarcoma Panel showed no fusion in one of the samples, where enough material was evaluable for RNA-Sequencing. Conclusions: Sporadic GISTs occur predominantly in the elderly (mean-age: 64.8 years) and are localized throughout the GI tract. In children and young adults suffering from a GIST in the stomach, the use of a SDHB-immunohistochemistry is helpful to screen for rare syndromic GISTs. Immunohistochemical markers including DOG1 and CD117 (using a panel of IHC markers) are reliable markers in GIST diagnosis. Further, molecular analysis is required for personalized treatment strategies.

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