Diagnostic Performance of Histopathology, Microbiological Methods, and Biomarkers in Periprosthetic Joint Infection: A Systematic Review With Contextual Surgical and Therapeutic Implications

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Periprosthetic joint infection (PJI) is among the most serious complications following total joint arthroplasty and remains diagnostically challenging because no single investigation reliably confirms or excludes infection across all clinical phenotypes.This systematic review evaluated the diagnostic performance of histopathology, microbiological methods, and serum and synovial biomarkers in PJI, with surgical and therapeutic implications considered contextually.The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework.PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to August 1, 2026, with backward citation searching.The formal evidence set was restricted to primary clinical diagnostic, cohort, and comparative studies; systematic reviews, meta-analyses, and narrative reviews were excluded from the primary evidence synthesis and used only for contextual interpretation and citation searching.Primary diagnostic studies were appraised using QUADAS-2, while non-diagnostic cohort and comparative evidence was appraised using ROBINS-I.Because of substantial clinical and methodological heterogeneity, a structured narrative synthesis was performed without a de novo meta-analysis.A total of 1,504 records were identified, 421 duplicates were removed, 1,083 records were screened, and 236 full-text reports were assessed.After excluding 223 full-text reports, 13 primary studies were included in the qualitative synthesis.Included studies supported the high confirmatory value of histopathology, improved microbiological yield with optimized culture and sonication, and clinically useful performance of synovial biomarkers and molecular tests in selected settings.For example, frozen section histology demonstrated 73.7% sensitivity and 98.8% specificity in one included cohort, sonicate fluid culture achieved 78.5% sensitivity compared with 60.8% for tissue culture in a landmark prospective study, and synovial C-reactive protein showed an area under the curve of 0.951 with 74.2% sensitivity and 98.0% specificity.Overall, PJI diagnosis is most reliable when histopathology, microbiology, biomarkers, clinical presentation, infection chronicity, implant stability, and operative findings are integrated; no single test should independently dictate implant retention, explantation, or reimplantation.