Background: Cystic echinococcosis rarely involves the pancreas and may mimic common cystic neoplasms. Recognition of characteristic imaging signs is central to diagnosis; the “water-lily” sign (floating detached endocyst) is a rare and highly characteristic finding in favor of transitional-stage hydatid cyst and, when recognized, can prevent inappropriate cyst puncture and guide stage- and anatomy-based management. Case: A 34-year-old woman from Iran, an endemic region for cystic echinococcosis, presented with intermittent epigastric/right upper quadrant pain. At an outside institution, endoscopic ultrasound-guided fine-needle aspiration had been performed before referral; cyst-fluid amylase was 20 U/L and carcinoembryonic antigen was not detected, arguing against pseudocyst and mucinous neoplasm. Ultrasound and MRI/MRCP performed after EUS showed a unilocular pancreatic head cyst with a floating internal membrane (“water-lily”/“serpent” appearance) and mild upstream pancreatic duct dilatation. Our multidisciplinary team favored pancreatic cystic echinococcosis. The patient underwent surgical cyst excision with avoidance of scolicidal instillation into the biliary tree. Albendazole (400 mg twice daily, ∼ 10-15 mg/kg/day) was given perioperatively and continued for 6 months. Pathology confirmed laminated membranes and protoscolices. She remains asymptomatic on surveillance MRI without recurrence. Conclusion: In an endemic region, a pancreatic cyst with a floating membrane and low cyst-fluid amylase should raise suspicion for cystic echinococcosis. Anchoring the diagnosis to WHO staging and resisting routine EUS-FNA can avert spillage and caustic cholangiopathy from scolicidal agents. Radiologists play the key role in making this distinction.

Rare subtypes of gastroesophageal malignancies represent a small but biologically meaningful fraction of upper gastrointestinal cancers. Although most therapeutic algorithms are derived from conventional squamous cell carcinoma and adenocarcinoma, uncommon entities such as variants of squamous cell carcinoma, lymphoepithelioma-like carcinoma, adenosquamous carcinoma, neuroendocrine carcinoma, and others display distinct clinicopathologic, immunologic, and molecular features that may influence prognosis and therapeutic decision-making. This review synthesizes current evidence regarding the epidemiology, histopathology, molecular alterations, and emerging therapeutic vulnerabilities across these rare subtypes. Importantly, these tumors frequently exhibit aggressive clinical behavior and are often managed by extrapolation from more common histologies due to the absence of prospective data. Increasing integration of genomic profiling, immune characterization, and biomarker-driven stratification is essential to refine diagnoses, expand precision therapeutic strategies, and improve outcomes. Recognition of these rare subtypes in routine practice is critical, as even small molecularly defined populations may carry disproportionate biological and translational significance within oncology.