Prognostic and Clinicopathological Significance of CD74 Expression in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, and reliable prognostic biomarkers are urgently needed to guide risk stratification and treatment. CD74 has been implicated in tumor progression, invasion, and pro-inflammatory signaling in various cancers. This systematic review and meta-analysis aimed to evaluate the association between CD74 expression and key clinicopathological features and survival outcomes in patients with PDAC. A systematic literature search was conducted in PubMed, Web of Science, and Scopus to identify eligible studies reporting on CD74 expression in PDAC tissues (PROSPERO: CRD420261402709). Studies were selected following the PRISMA 2020 guidelines. The methodological quality of the included studies was assessed using the QUIPS tool. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the associations between CD74 expression and perineural invasion (PNI), lymphatic invasion, lymph node metastasis (pN), vascular permeation, pTNM stage, and overall survival. Statistical analyses were performed using Review Manager v5.4. DerSimonian–Laird random-effects models were applied as sensitivity analysis for every outcome, with Mantel–Haenszel fixed-effects models as the primary analysis according to the level of heterogeneity, which was quantified using the I2 statistic. A total of 83 records were initially identified, of which five studies met the inclusion criteria and were included in the quantitative synthesis. CD74-positive expression was significantly associated with an increased risk of perineural invasion (four cohorts, 351 patients; OR = 3.69; 95% CI: 2.27–5.99; p < 0.00001; I2 = 0%), lymphatic invasion (four cohorts, 351 patients; OR = 2.05; 95% CI: 1.21–3.46; p = 0.007; I2 = 0%), and lymph node metastasis (four cohorts, 462 patients; OR = 1.94; 95% CI: 1.27–2.96; p = 0.002; I2 = 0%). A non-significant trend toward increased vascular permeation (three cohorts, 181 patients; OR = 1.99; 95% CI: 0.84–4.68; p = 0.12; I2 = 0%) and advanced pTNM stage (three cohorts, 284 patients; OR = 1.62; 95% CI: 0.93–2.82; p = 0.09; I2 = 0%) was also observed. Importantly, CD74 positivity was significantly associated with worse overall survival (three cohorts, 293 patients; HR = 2.04, 95% CI: 1.45–2.88; p < 0.00001; I2 = 0%). This analysis was structured into two subgroups: HR = 2.21 (95% CI: 1.50–3.25) in the two cohorts contributing multivariable-adjusted, immunohistochemistry-based estimates, and HR = 1.52 (95% CI: 0.72–3.21) in the single cohort contributing a univariable estimate reconstructed from transcript-level data, with no significant difference between the subgroups (p = 0.38). Because the estimated between-study variance was zero for every outcome, random-effects estimates were almost identical to the fixed-effects estimates throughout. As the pooled survival estimate combines adjusted with unadjusted estimates, it describes a prognostic association rather than established independent prognostic value. This meta-analysis demonstrates that elevated CD74 expression in PDAC is significantly associated with perineural invasion, lymphatic invasion, lymph node metastasis, and poorer overall survival, supporting an association with an adverse prognostic. Because the evidence base comprises few retrospective cohorts that used different, non-standardized thresholds to define CD74 positivity and different definitions of several outcomes, these findings should be regarded as hypothesis-generating: they identify CD74 as a candidate for prospective validation and mechanistic investigation rather than as an established biomarker for risk stratification or therapeutic decision-making. Further large-scale prospective studies are warranted to validate these results and explore the clinical utility of CD74-targeted strategies.