CLINICOPATHOLOGICAL CORRELATION OF HISTOPATHOLOGICAL FEATURES WITH MICROBIOLOGICAL DIAGNOSIS, DISEASE SEVERITY, TREATMENT RESPONSE, AND CLINICAL OUTCOMES IN PULMONARY AND EXTRAPULMONARY TUBERCULOSIS: A SYSTEMATIC REVIEW

Abstract

Background: Histopathological examination is central to the diagnosis of tuberculosis, particularly in extrapulmonary and paucibacillary disease. Classical features such as epithelioid-cell granulomas, Langhans-type giant cells, and caseous necrosis strongly support tuberculosis but are not entirely specific. Microbiological confirmation by acid-fast bacillus microscopy, culture, or nucleic-acid amplification testing may remain negative, and the relationship between histological morphology, disease severity, treatment response, and clinical outcome is not fully established. Objective: To systematically evaluate the correlation of histopathological features with microbiological diagnosis, disease severity, treatment response, and clinical outcomes in pulmonary and extrapulmonary tuberculosis. Methods: A systematic review was conducted according to PRISMA 2020 guidelines. MEDLINE/PubMed, Embase, Scopus, Web of Science, Cochrane Library, CINAHL, Global Index Medicus, and Google Scholar were searched from inception to January 2026. Studies evaluating tissue or cytological histopathology in relation to acid-fast bacillus staining, mycobacterial culture, polymerase chain reaction, Xpert MTB/RIF, Xpert MTB/RIF Ultra, disease-severity indicators, treatment response, relapse, failure, disability, or mortality were included. Two reviewers independently screened studies, extracted data, and assessed methodological quality. Random-effects meta-analysis was planned where sufficiently homogeneous data were available. Results: Twelve studies were included in the qualitative synthesis, of which eight contributed to quantitative analysis. Necrotizing, suppurative, and predominantly necrotic histological patterns generally showed higher microbiological positivity than well-formed non-necrotizing granulomas. Acid-fast bacillus staining demonstrated high specificity but low sensitivity, especially in extrapulmonary specimens. Culture and molecular assays improved confirmation when used alongside histopathology. Poorly formed granulomas, extensive necrosis, and higher tissue bacillary density were more frequently reported in immunocompromised patients and were associated in some studies with greater disease severity and prolonged treatment. However, direct evidence linking baseline histological morphology with treatment failure, relapse, disability, or mortality was limited and heterogeneous. Conclusion: Histopathology and microbiology are complementary in tuberculosis diagnosis. Caseous necrosis and granulomatous inflammation provide strong diagnostic support, but microbiological confirmation remains necessary whenever possible, particularly for drug-resistance assessment. Negative microbiology does not exclude tuberculosis, especially in extrapulmonary disease. Current evidence is insufficient to use any single histopathological pattern as an independent predictor of treatment response or long-term clinical outcome.