PDGRFA-mutant gastrointestinal stromal tumours (GISTs) in Eastern England: clinicopathological features and outcomes of 50 patients diagnosed between 2008-2021

BackgroundPDGRFA-mutant gastrointestinal tumours (GISTs) comprise approximately 10% of GISTs and are mostly gastric. Targeted therapies against these tumours have historically been limited by tyrosine kinase inhibitor (TKI)-resistance. We reviewed the characteristics and outcome of all PDGRFA-mutant patients seen at our centre over the last 13 years. MethodsAll PDGRFA-mutant patients seen at the Cambridge University Hospitals NHS Foundation Trust GIST clinic from July 2008-July 2021 were retrospectively reviewed and followed up. Results50 PDGRFA-mutant GIST patients were diagnosed during the 13-year period. 60% were male. Median tumour size was 5 cm and the majority were epithelioid (44%) or mixed (36%) type. Commonest primary location was the gastric body (52%). In non-metastatic patients the low-risk modified AFIP risk group was the most common (65.2%). PDGFRA exon 18 (86%) were the most common PDGFRA mutations, most being imatinib resistant. None harboured a KIT mutation. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were positive for DOG1 (94%). CD34 was highly expressed in 48% of cases. 13% developed metastases during the 13-year follow-up period: liver (80%) being the commonest site. 76% of all patients underwent radical resection. 14% received TKI therapy. After a median follow-up of 55.1 months, 82% remained alive: 6 patients died from metastatic GIST; 3 from other causes. Median time to metastatic disease was 30.1 months, and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had the poorest survival outcome (p=0.001) ConclusionTo date this is the largest single-centre European PDGRFA-mutant GIST cohort. Results highlight the generally indolent nature of PDGRFA-mutant disease (contrasted to the poor outcome of those who present with metastatic disease), male and gastric preponderance (unlike KIT-mutant GISTs), and variable KIT expression. HighlightsO_LILargest single-centre European PDGFRA-mutant GIST series (n=50) to date C_LIO_LIResults confirm the relative indolent nature of non-metastatic PDGFRA-mutant GISTs C_LIO_LIPDGFRA-mutant GISTs had variable levels of KIT protein expression (immunohistochemistry) despite being KIT-wild type. C_LIO_LIIn contrast to KIT-mutant GISTs, PDGFRA-mutant GISTs were more common in males and less frequent in parts of the stomach where KIT-mutant GISTS occur. C_LIO_LIA minority of patients received TKI therapy. One patient with metastatic imatinib-resistant PDGFRA-mutant GIST had a 6 year response to imatinib. C_LI