Diagnostic Accuracy of Soft Tissue Cytology and Risk of Malignancy Across the IAC-IARC-WHO Six-Tier Reporting System:...

Cytology of soft tissue tumours poses a diagnostic challenge due to their morphological heterogeneity and cytomorphological overlap between benign and malignant lesions. The IAC-IARC-WHO Reporting System for Soft Tissue Cytopathology introduces a standardised six-tier diagnostic framework aligned with the WHO Classification of Tumours. This systematic review and meta-analysis aimed to evaluate the overall diagnostic accuracy of soft tissue cytology and to determine the pooled risk of malignancy (ROM) for each WHO category, thereby assessing the clinical utility of this reporting system as a risk-stratified framework for the management of soft tissue lesions.

A systematic literature search was conducted in PubMed and other electronic databases till February 2026, with no date restrictions, following the PRISMA-DTA guidelines. The studies reported soft tissue cytology cases with the histopathological confirmation and had sufficient categorical detail to map to the IAC-IARC-WHO reporting system; they were eligible for inclusion. Data extraction, category mapping and quality assessment using the QUADAS-3 were performed. The pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-) and diagnostic odds ratio (DOR) were estimated using a bivariate random-effects model. Hierarchical summary receiver operating characteristic (HSROC) curves were generated, and I² statistics were used to assess heterogeneity. Subgroup analyses were performed for cytology method, geographic origin and study design. Meta-regression was conducted using histopathological verification rate, malignancy prevalence and publication year as covariates. The pooled ROM for WHO categories was calculated, and the certainty of evidence was assessed using the GRADE framework.

Thirty-seven studies were included; About 32 studies, comprising of 6773 histologically verified cases, were analysed for diagnostic accuracy. The pooled sensitivity was 84.9%, the pooled specificity was 96.8% and the overall diagnostic accuracy was 92.79%. The LR+ was 26.85, the LR- was 0.155 and the DOR was 172.7. The pre-test probability was 41.3%, and the post-test probability of malignancy was raised to 95%, while a negative result reduced it to 10%. The pooled ROM observed was 26.4%, 4.8%, 31.6%, 48.5%, 74.5% and 93.5% for the insufficient/non-diagnostic/inadequate, benign, atypical, STNUMP, suspicious for malignancy and malignant categories, respectively. Significant heterogeneity was observed in sensitivity (I² = 69%), whereas moderate heterogeneity was observed in specificity (I² = 49%). No significant publication bias was detected, and the GRADE certainty of evidence was rated very low (⊕◯◯◯) due to serious concerns in the risk of bias, indirectness and inconsistency domains.

The present study demonstrates high specificity and an increase in ROM from the benign category, followed by the insufficient/non-diagnostic/inadequate category and the malignant categories, confirming validity and supporting the role of cytology as a reliable malignancy-confirmation tool and risk-stratified decision-support system in the preoperative management of soft tissue tumours. The very-low grade certainty was due to incomplete histopathological verification, retrospective study designs and inadequate blinding in most included studies, underscoring the need for well-designed prospective studies that use the WHO soft tissue cytology reporting system and include complete histopathological follow-up to generate high-certainty evidence for clinical guideline development.