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BACKGROUND This article presents a rare case of pancreatic cancer complicated by a leukemoid reaction, alongside 4 similar cases treated at our hospital between 2016 and 2024. Leukemoid reactions are uncommon paraneoplastic manifestations, and their optimal management remains undefined. Herein, we systematically analyze the clinical characteristics and potential molecular mechanisms involved in the development and progression of tumor-associated leukemoid reactions, and summarize our diagnostic and therapeutic approaches. CASE REPORT We reviewed the records of 5 patients at our hospital who had malignancies complicated by leukemoid reactions. Medical histories, laboratory tests, imaging findings, bone marrow biopsy results, and treatment details were collected and analyzed. We explored the pathogenesis, diagnostic strategies, and treatment modalities for leukemoid reactions. A 52-year-old man with advanced pancreatic adenocarcinoma and a KRAS p.G12D mutation, developed extreme leukocytosis (96.22×10⁹ white blood cells/L) in the context of hepatic metastases. Despite broad-spectrum antimicrobial coverage, cytoreductive therapies, and supportive measures (bilirubin adsorption and plasma exchange, continuous veno-venous hemofiltration), his condition rapidly deteriorated, culminating in multi-organ failure. The 4 additional patients - 1 each with metastatic breast cancer, colon cancer, cholangiocarcinoma, and recurrent pancreatic cancer - exhibited similarly aggressive courses, with only transient stabilization observed in the breast cancer case. CONCLUSIONS Patients with malignancies complicated by leukemoid reaction generally have a poor prognosis. Clinicians should be alert to markedly elevated white blood cell counts, promptly investigate underlying causes, and initiate individualized treatments. Future research should focus on the molecular mechanisms driving the development and progression of leukemoid reactions and therapeutic interventions to enhance patient survival and clinical outcomes.