ONCOGENIC MICROORGANISMS AND HUMAN CARCINOGENESIS: A SYSTEMATIC REVIEW OF PATHOGENIC MECHANISMS AND HISTOPATHOLOGICAL CHANGES

Abstract

Background A defined group of viruses, bacteria, and parasites contributes directly or indirectly to human carcinogenesis. These microorganisms may express oncogenic proteins, integrate into the host genome, promote chronic inflammation, alter immune surveillance, induce genomic and epigenetic injury, and create tissue environments that support clonal expansion. These biological processes are reflected in characteristic precursor lesions and histopathological patterns. Objective: This systematic review examined the pathogenic mechanisms through which oncogenic microorganisms contribute to human cancer and correlated these mechanisms with sequential histopathological changes. It also evaluated the diagnostic importance of demonstrating microorganisms or validated surrogate markers within neoplastic tissue. Methods: PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched from database inception to January 31, 2026. Supplementary searches were conducted through Google Scholar, International Agency for Research on Cancer resources, citation tracking, and manual screening of reference lists. Human epidemiological studies, clinicopathological investigations, molecular tumour studies, prospective cohorts, intervention studies, and selected mechanistic studies using human-derived material were eligible. Two reviewers independently screened records, extracted data, and evaluated methodological quality. Owing to substantial heterogeneity in microorganisms, tumour types, detection methods, and pathological outcomes, the evidence was synthesised narratively. Results: The search identified 2,764 records, including 2,698 records from electronic databases and 66 records from supplementary sources. After removal of 712 duplicate records, 2,052 titles and abstracts were screened. Of these, 1,861 records were excluded, and 191 reports were sought for full-text retrieval. Eleven reports could not be obtained, leaving 180 full-text articles for eligibility assessment. A total of 150 reports were excluded for predefined reasons, and 30 studies were included in the qualitative synthesis. No meta-analysis was performed because of substantial heterogeneity in microorganisms, tumour sites, study designs, laboratory methods, and pathological outcomes. The strongest evidence involved high-risk human papillomavirus, Epstein–Barr virus, hepatitis B and C viruses, human T-cell lymphotropic virus type 1, Kaposi sarcoma-associated herpesvirus, Merkel cell polyomavirus, Helicobacter pylori, Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis sinensis. Four principal carcinogenic patterns were identified: direct disruption of cell-cycle and apoptotic control, viral persistence or integration with clonal selection, chronic inflammation with regenerative proliferation, and antigen-driven or immunodeficiency-facilitated neoplasia. These mechanisms corresponded to recognisable histopathological pathways, including intraepithelial neoplasia, atrophy–metaplasia dysplasia progression, chronic hepatitis–cirrhosis–dysplastic nodule evolution, lymphoid clonal expansion, vascular spindle-cell proliferation, parasite-associated squamous metaplasia, and biliary dysplasia. Conclusions: Microorganism associated cancers arise through distinct but overlapping pathways connecting persistent infection with molecular injury, altered immunity, tissue remodelling, and clonal evolution. Histopathology provides a visible record of these processes and remains essential for distinguishing active microbial carcinogenesis from incidental microbial detection. Prevention, treatment, and control of oncogenic infections offer major opportunities to reduce the global cancer burden.