INTRODUCTION: Synovial sarcoma (SS) is an uncommon subtype of mesenchymal derived solid tumors that is characterized by its unique histologic pattern. It is most often found in the extremities and rarely, the digestive tract, which can lead to gastrointestinal bleeding. Gastric tumors of mesenchymal origin often have overlapping radiographic and endoscopic appearances, which presents a significant challenge in diagnosis. We report one of only 3 confirmed cases of primary gastric synovial sarcoma of the lesser curvature in a patient who presented with hematemesis. CASE DESCRIPTION/METHODS: A 26-year-old male presented with a two-week history of worsening abdominal pain and intermittent hematemesis. He denied any history of hematochezia, melena, early satiety, weight loss, recent NSAID use or alcohol ingestion. Exam was notable for epigastric tenderness without rebound or guarding. Labs revealed microcytic anemia and thrombocytopenia without transaminitis or elevated lipase. Abdominal CT showed an 8 cm mass along the posterior gastric body with suspicion for intratumoral hemorrhage, highly suggestive of a gastrointestinal stromal tumor (GIST) [Figure 1]. EGD revealed a large, ulcerated, non-bleeding, non-circumferential, submucosal mass on the lesser curvature of the stomach, also concerning for a GIST [Figure 2]. Endoscopic ultrasound showed neither hepatic invasion nor lymphadenopathy. Partial gastrectomy pathology supported the endoscopic biopsy results, which showed high grade, monophasic, atypical spindle cells with t(X;18)(SYT-SSX) chromosomal translocation by fluorescence in situ hybridization (FISH). Immunohistochemistry (IHC) was strongly positive for TLE1 staining, but negative for C-KIT and DOG-1, to which GISTs are immunoreactive, confirming a diagnosis of primary gastric synovial sarcoma [Figure 3]. He tolerated 6 cycles of sarcoma-directed chemotherapy without evidence of progressive disease. DISCUSSION: Intramural gastric spindle cell malignancies are difficult to distinguish from one another, and require different disease-tailored therapies. Though GISTs account for 90% of these tumors, other rare pathologies exist. These include synovial sarcomas, which are characterized by a variable degree of epithelial differentiation associated with a disease-specific gene translocation. In patients with hematemesis found to have endoscopic and radiographic findings suspicious for GIST, ICH and FISH analyses are crucial to differentiate between mesenchymal malignancies to guide effective therapy.

Lung carcinoma is the second most common malignancy in both men and women, and may metastasize to the orbit relatively early in the disease course. Metastasis to the optic nerve or its sheath is an exceedingly rare occurrence, and diagnosis may be complicated by nonspecific clinical and radiographic features. The authors present a case of squamous cell lung cancer metastatic to the optic nerve sheath, initially diagnosed as optic neuritis based on its equivocal clinical and radiographic features. This is the first histopathologically confirmed case of squamous cell lung cancer metastatic to the optic nerve sheath in the literature.

11514 Background: Tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for advanced GIST via pharmacologic targeting of driver oncogenes such as KIT. Detection of KIT alterations through tissue-based next-generation sequencing (NGS) is common, but circulating tumor DNA (ctDNA)-based NGS is a less invasive alternative to identify driver and resistance mutations in advanced GIST. Patients (pts) with KIT-mutant GIST benefit from first-line (1L) imatinib; however, KIT resistance mutations may confer imatinib-resistance and differential sensitivity to subsequent TKIs. We sought to analyze ctDNA from GIST pts to determine whether certain resistance mutations were associated with superior outcomes with particular TKIs in the second-line and beyond (2L+). Methods: Under an approved institutional review board protocol, a retrospective analysis was performed with available ctDNA NGS results (Guardant360; Redwood City, CA) from pts (N = 104) who progressed on 1L imatinib between 2017-21. Using R statistical programming, we identified pts with primary KIT alterations (N = 64) and known resistance mutations in KIT exons 13 (N = 25) and 17 (N = 35). We studied the median time to treatment failure (mTTF), defined as the time from treatment start to treatment end (months) due to progressive disease or toxicity, for each 2L+ drug. Using Kaplan-Meier methods, we calculated Cox proportional-hazard ratios (HR) with confidence intervals (CI) and p-values for statistical significance. Results: 49% were male (median age 66; range, 31-94). Driver oncogenes were detected in 80% (N = 83), including KIT, NF1, PDGFRA and BRAF. Of those with a KIT alteration, 12 (19%) had KIT exon 9 mutations and 52 (81%) had KIT exon 11 mutations. KIT resistance mutations were observed in KIT exons 13 (N = 25; V654), 14 (N = 2; T670), and 17 (N = 45; D816, D820, N822, Y823). Pts with KIT resistance mutations received 2L+ therapy with avapritinib, dose-escalated imatinib, nilotinib, pazopanib, ponatinib, regorafenib, ripretinib, or sunitinib. mTTF for KIT exon 13 V654 pts treated with 2L+ sunitinib, imatinib 800mg, or other was 10.8, 7.5, and 3.7 months, respectively. TTF for sunitinib vs other 2L+ drugs showed a HR of 0.51 (CI 0.33-0.8), p = 0.003. mTTF for KIT exon 17 (non-V654) pts treated with 2L+ regorafenib, imatinib 800mg, or other was 4.6, 1.2, and 6.3 months, respectively. Comparison of mTTF for regorafenib vs other 2L+ drugs was not statistically significant. Conclusions: ctDNA is a noninvasive tool for detecting driver and resistance mutations in pts with advanced GIST. GIST pts with KIT exon 13 V654 resistance mutations had superior outcomes in the 2L+ setting with sunitinib. Regorafenib was not superior to other 2L+ TKIs in pts with KIT exon 17 resistance mutations, possibly due to their own activity against exon 17 resistance alterations. ctDNA-guided therapy warrants evaluation in a prospective clinical trial.

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