Introduction: Primary squamous cell carcinoma (SCC) of the pancreas is an exceptionally rare entity, as the pancreas lacks native squamous epithelium. According to SEER database, the incidence of SCCP is low, accounting for 0.5–5% of exocrine pancreatic tumors. Its pathogenesis remains unclear, and diagnosis requires meticulous exclusion of metastatic SCC from more common primary sites. We present a case of primary pancreatic SC, illustrating the difficulties in establishing diagnosis and determining therapeutic strategy.

Case Presentation: A 66-year-old woman, non-smoker, with previous osteoarthritis and depression, presented with long-standing lumbar pain attributed to known spinal disease. Over the preceding three months, she developed progressively worsening left upper quadrant pain radiating posteriorly, with characteristics distinct from her baseline pain. She denied jaundice, pruritus, gastrointestinal symptoms, weight loss, or constitutional complaints. Laboratory studies showed leukocytosis (13,300/µL) and mild hyponatraemia (131 mmol/L), with normal liver function, pancreatic enzymes, bilirubin, and inflammatory markers. An initial non-contrast CT revealed focal thickening at the pancreatic body–tail junction, suspicious for neoplasia. A contrast-enhanced CT performed subsequently demonstrated a heterogeneous mass in the distal body/tail. suspicious for pancreatic adenocarcinoma. Tumor markers CEA 22 ng/ml and CA 19.9 3262 U/ml supported the hypothesis. Endoscopic ultrasound identified a 63×52 mm predominantly hypoechoic, heterogeneous lesion involving the distal pancreatic body and tail, with invasion of the splenic artery and vein and the porto-spleno-mesaraic confluence. Multiple suspicious celiac and perilesional lymph nodes were observed. No ascites was detected. Fine-needle biopsy (22G) yielded cohesive epithelial cells with dense cytoplasm and marked nuclear atypia. Immunohistochemistry showed positivity for AE1/AE3, CK7, and p40, supporting the diagnosis of primary squamous cell carcinoma of the pancreas. Surprisingly, no adenocarcinoma component was identified. A comprehensive staging workup excluded extrapancreatic origin. The case was discussed at the multidisciplinary tumour board, which classified the tumour as borderline resectable, due to involvement of the splenic vessels, thus recommended neoadjuvant chemotherapy with the intention of achieving potential resectability.

Conclusion: This case highlights the rarity and aggressive behaviour of primary pancreatic SCC and the essential role of multidisciplinary evaluation to tackle the poor prognosis. Different therapeutic approaches including surgery, chemotherapy, radiotherapy, anti-angiogenic therapies, and immune checkpoint inhibitors have been explored with mixed results. Except for surgery, which offers the most significant survival benefit, available treatments have demonstrated limited efficacy in managing SCC of the pancreas.