Background: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms characterized by epithelioid or spindle cells co-expressing melanocytic and smooth muscle markers. Pancreatic PEComas are exceedingly uncommon, with limited data guiding diagnosis and management. Mutations in TSC1/TSC2 lead to mTOR pathway activation, identifying a potential target for mTOR inhibitors such as everolimus and temsirolimus. Accurate endoscopic ultrasound (EUS) evaluation and molecular profiling are critical for diagnosis and therapeutic planning. 

Case Presentation: A 37-year-old woman undergoing pelvic MRI for chronic pelvic pain was found to have a 4.1 cm enhancing mass at the inferolateral aspect of the pancreatic head. Cross-sectional imaging and ^68Ga-DOTATATE PET were indeterminate for neuroendocrine tumor. EUS revealed a well-defined, hypoechoic lesion without vascular invasion or ductal dilation. EUS-guided fine-needle biopsy (FNB) demonstrated epithelioid cells with eosinophilic cytoplasm and absent atypia, mitoses, or necrosis. Immunohistochemistry showed strong positivity for HMB-45, Melan-A, MITF, and SMA, with patchy desmin, consistent with PEComa. Next-generation sequencing identified a pathogenic TSC2 frameshift mutation (p.R1355Wfs*60), microsatellite stability, and low tumor mutational burden (4.4 mut/Mb). The presence of a concurrent left renal angiomyolipoma suggested possible syndromic association with tuberous sclerosis complex (TSC). The patient underwent robotic-assisted enucleation, and final histopathology confirmed PEComa. A minor postoperative pancreatic leak resolved with conservative management. 

Discussion: EUS-FNB plays a pivotal role in the minimally invasive diagnosis of pancreatic PEComa, enabling both histologic and molecular characterization. The identified TSC2 mutation confirms mTOR pathway dysregulation, supporting the rationale for targeted therapy with mTOR inhibitors in unresectable or recurrent disease. Prior reports demonstrate durable responses to everolimus and temsirolimus, highlighting their emerging role in the management of PEComas. In this case, complete resection achieved curative outcome, but the genomic findings underscore the importance of precision oncology in follow-up planning. 

Conclusion: This case illustrates the diagnostic utility of EUS-guided biopsy coupled with molecular profiling in identifying pancreatic PEComa with actionable TSC2 mutation. Integration of EUS pathology and genomic testing not only establishes definitive diagnosis but also guides potential targeted therapy. Recognition of TSC-related features is essential for comprehensive evaluation and multidisciplinary management.