Granulomatous Inflammation in Tissue Biopsies: Etiological Spectrum and Diagnostic Performance of Histochemical and Molecular Methods – A Systematic Review and Meta-analysis

Granulomatous inflammation is a distinctive histopathological response characterized by the formation of granulomas composed of epithelioid histiocytes, multinucleated giant cells, and surrounding lymphocytes. It represents an important tissue reaction to a variety of infectious and non-infectious etiologies, including tuberculosis, fungal infections, sarcoidosis, autoimmune diseases, and foreign body reactions. Identification of the underlying cause of granulomatous inflammation remains a diagnostic challenge, particularly in cases where the causative organism is scarce or absent in routine histological sections. In such situations, histochemical staining techniques and molecular diagnostic methods play an essential role in improving etiological detection.

The present study aimed to systematically review the etiological spectrum of granulomatous inflammation in tissue biopsies and evaluate the diagnostic performance of histochemical stains and molecular methods in identifying specific causes. A comprehensive literature search was performed using PubMed, Scopus, Web of Science, and Google Scholar databases for studies published between 2000 and 2025. Studies reporting granulomatous inflammation diagnosed through histopathology and evaluated using histochemical stains such as Ziehl–Neelsen (ZN), periodic acid–Schiff (PAS), Grocott methenamine silver (GMS), and Fite–Faraco stain, as well as molecular techniques such as polymerase chain reaction (PCR), were included.

A total of 36 studies involving more than 7,200 biopsy specimens were included in the final analysis. Infectious causes accounted for approximately two-thirds of granulomatous lesions, with tuberculosis being the most frequently reported etiology. Histochemical staining techniques demonstrated variable diagnostic yields, with Ziehl–Neelsen staining showing positivity in approximately 20–35% of tuberculous granulomas. PAS and GMS stains were useful in identifying fungal organisms, whereas Fite–Faraco staining was helpful for detecting Mycobacterium leprae. Molecular techniques such as PCR significantly improved the detection of infectious etiologies, particularly in paucibacillary lesions.

Overall, the findings highlight that granulomatous inflammation represents a heterogeneous group of conditions with diverse etiological factors. A combined diagnostic approach integrating histopathology, special stains, and molecular techniques enhances diagnostic accuracy and facilitates appropriate clinical management. Further multicenter studies with standardized diagnostic protocols are needed to refine the diagnostic approach to granulomatous diseases.