(P 171) GASTROINTESTINAL STROMAL TUMOURS (GISTS) IN NEUROFIBROMATOSIS TYPE (NF1): A SINGLE-CENTER OBSERVATIONAL RETROSPECTIVE STUDY

Objective: While most Gastrointestinal Stromal Tumours (GISTs) are sporadic, those occurring in the context of neurofibromatosis type 1 (NF1) are very rare, having a pathogenic mechanism that is independent of c-KIT and PDGFRA. Currently, available data on this subgroup of patients are very limited and primarily based on small case reports. This retrospective observational study explored the natural history and clinical outcome of a series of such patients treated at a single reference center.

Methods: We retrospectively collected clinical data from all patients diagnosed with GIST and clinically or molecularly diagnosed with NF1, who were treated and followed up at our center from January 2001 to April 2024.

Results: 37 patients were included in our series, of which 25 (67%) were women. The median age was 49 years (range 34-75). Except for three patients, all showed signs of clinical NF1. In 83% of patients, the primary tumour developed in the small intestine, while 11% had tumours of gastric origin. In 3 patients, a mutation in the c-KIT gene was detected. At diagnosis, 60% of patients presented with multifocal disease, and only 4 patients had peritoneal metastatic disease.. In 55% of patients, GISTs were discovered incidentally during diagnostic work-up or follow-up for other malignancies. All patients, including the 4 with metastatic disease, were treated with surgery. 1 out of the 4 patients with metastatic disease at diagnosis maintained surgical remission until the time of analysis.
Only 7 patients with unresectable relapse of disease received medical therapy with tyrosine kinase inhibitors (Sunitinib and Regorafenib). Median DFS at 20 years was 8.3 years, while median OS was 9.2 years. There was no significant difference in OS between patients with single vs multifocal lesions at diagnosis or between those diagnosed incidentally versus those who were symptomatic. However, OS tended to be better in patients with incidental diagnoses and multifocal lesions. There was no statistically significant difference in OS between the relapsed and non-relapsed populations. Only one half of patients who were deceased at the time of the analysis had died from GIST. DFS was significantly different (P < 0.001) in patients stratified by risk (< or > 50%) according to Joensuu's prognostic maps. 15 patients (40.6%) experienced a relapse locally or at a distant site, with a median interval to relapse of 3.1 years (range 3.7 months to 14.5 years). Regarding medical treatment, 7 patients were treated with sunitinib and median PFS was 5.2 months (95% CI: 2.5-9.2). Only 3 received second line treatment with regorafenib: 1 of them relapsed after 2 months from treatment start, the other 2 continued treatment for more than 12 months.

Conclusion: Patients with NF1 and GISTs represent a rare subgroup. In our series, three patients had c-KIT mutations, which could potentially indicate sporadic GISTs occurring coincidentally in the context of NF1. As expected most of the tumours developed in the small intestine, although 11% were of gastric origin. DFS and OS of patients with a relapsed disease was comparable to those without recurrence and reasonably high in the medium-long term. In patients with unrespectable relapse of disease, medical treatments had a very limited efficacy and prognosis was poor. The prognostic factors used in clinical practice for sporadic GISTs were also prognostic in this subgroup. Multifocality at diagnosis was not an unfavorable prognostic factor. A significant number of secondary malignancies were found, but there may have been a selection bias, in addition to the underlying condition. A multicenter observational study involving reference centers in Italy is underway to expand this study.