Diagnosis
Diagnosis
Gastrointestinal stromal tumor (GIST), mixed spindle and epithelioid type.
Discussion
The differentiation of a malignant neoplasm of unknown origin can be challenging, particularly in cases where the clinical presentation or imaging findings are equivocal and the histological examination reveals multiple unique patterns.
GIST is a mesenchymal neoplasm with variable behavior, and may arise throughout the GI tract, though most commonly in the stomach and small intestine. In rare instances, GIST may arise in extraintestinal locations. GISTs are believed to originate from interstitial cells of Cajal or their stem cell-like precursors, and the majority are driven by a sporadic KIT or PDGFRα mutation. KIT mutations account for 75-80% of sporadic mutations in GIST, while PDGFRα mutations account for approximately 10%. Clinically, there is no pathognomonic feature of GIST, and symptoms are highly variable depending on tumor size and location. However, the most common presenting symptom is GI bleeding, either acute or chronic. GIST may occur at any age, though peak incidence is in the sixth decade of life.
Grossly, GIST can vary in appearance. Small GISTs often form a solid, subserosal, or intramural mass. Large GISTs more classically form external, sometimes pedunculated masses that may be centrally cystic with areas of necrosis and hemorrhage.
Histologically, GIST has three main morphologic patterns: spindle cell (~70%), epithelioid (~20%), and mixed (~10%). Spindle type consists of bland spindle cells with faintly eosinophilic cytoplasm arranged in a syncytial pattern, with elongated nuclei and inconspicuous nucleoli. The epithelioid type is composed of round cells with clear to eosinophilic cytoplasm arranged in sheets or nests, and tends to demonstrate greater pleomorphism than the spindle type. Mixed tumors contain both spindle and epithelioid morphology.
The primary treatment modality of GIST is complete surgical resection with negative margins. However, a tyrosine kinase inhibitor (such as imatinib) is the first-line treatment for advanced, unresectable, metastatic, or recurrent GIST. Risk stratification for recurrence and the need for adjuvant therapy is based on tumor size, mitotic rate, and location.
The differential diagnosis in this case includes smooth muscle tumors such as leiomyosarcoma. These tumors show spindle cell morphology, but are positive for smooth muscle markers and negative for c-KIT and DOG1. Also in the differential are nerve sheath tumors such as schwannoma, inflammatory myofibroblastic tumor, and solitary fibrous tumor. Schwannomas show spindle cells which may form hypercellular and hypocellular areas (Antoni A and Antoni B). However, these tumors would be positive for S100, SOX10, and GFAP, while negative for c-KIT and DOG1. Inflammatory myofibroblastic tumors may show various histologic patterns similar to this case, and might show ALK positivity by IHC. Similarly, solitary fibrous tumors may show haphazard cells with eosinophilic cytoplasm, but show positive staining for CD34 and STAT6.
Resources
1- Gold J.S., Gönen M., Gutiérrez A. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10:1045–1052. doi: 10.1016/S1470-2045(09)70242-6.
2- Helbing A, Menon G. Gastrointestinal Stromal Tumors. [Updated 2025 Sep 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554541/
3- Landi B., Blay J.Y., Bonvalot S. Gastrointestinal stromal tumours (GISTs): French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO) Dig. Liver Dis. 2019;51:1223–1231. doi: 10.1016/j.dld.2019.07.006.
4- Mathias-Machado MC, de Jesus VHF, de Carvalho Oliveira LJ, Neumann M, Peixoto RD. Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications. Cancers (Basel). 2022 Oct 29;14(21):5330. doi: 10.3390/cancers14215330. PMID: 36358751; PMCID: PMC9656487.
5-Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006 May;23(2):70-83. doi: 10.1053/j.semdp.2006.09.001. PMID: 17193820.
6- Morgan J, Raut CP, Duensing A, Keedy VL. Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors. UpToDate. UpToDate Inc; 2026.
7- Rammohan A., Sathyanesan J., Rajendran K. A gist of gastrointestinal stromal tumors: A review. World J. Gastrointest. Oncol. 2013;5:102–112. doi: 10.4251/wjgo.v5.i6.102.
8- Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, García-Del-Muro X, Fernández-Hernández JÁ, Herrero L, López-Pousa A, Poveda A, Martínez-Marín V. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol. 2023 Aug 24;15:17588359231192388. doi: