Oncology · Medical Literature
Diagnostic accuracy and association with lymph node metastasis of the systemic immune-inflammation index in thyroid cancer: a systematic review and meta-analysis.
Abstract
The Systemic Immune-Inflammation Index (SII), a composite biomarker integrating neutrophil, platelet, and lymphocyte counts, has been increasingly investigated in thyroid cancer. However, its diagnostic accuracy and association with lymph node metastasis (LNM) remain uncertain. This study aimed to systematically evaluate the diagnostic performance of SII for thyroid cancer and its association with LNM. A systematic literature search was conducted across PubMed, Scopus, and Web of Science. A diagnostic meta-analysis using the bivariate Reitsma model was performed to pool sensitivity, specificity, likelihood ratios, and the area under the summary receiver operating characteristic curve (AUC). The association between SII and LNM was assessed by pooling mean differences (MD) using an inverse-variance random-effects model. Heterogeneity was evaluated using I² statistics and Cochran's Q test. This systematic review was registered in PROSPERO (PROSPERO 2025 CRD420251233710). Ten studies were included. The diagnostic meta-analysis (6 studies; 2,209 participants) yielded a pooled sensitivity of 76.8% (95% CI: 63.8-86.1%), specificity of 71.2% (95% CI: 54.9-83.4%), and AUC of 0.805. The positive and negative likelihood ratios were 2.78 and 0.34, respectively. The LNM meta-analysis (5 studies; 2,073 participants) demonstrated significantly higher SII in patients with LNM (MD = 102.87; 95% CI: 58.86-146.89; p < 0.00001; I² = 56%). Leave-one-out sensitivity analyses confirmed the robustness of both findings. Sensitivity analysis excluding one outlier study yielded consistent results with reduced heterogeneity (MD = 105.72; I² = 32%). SII demonstrates moderate diagnostic accuracy for thyroid cancer and is significantly elevated in patients with lymph node metastasis, supporting its potential as an adjunctive biomarker for diagnostic triage and preoperative risk stratification. Given substantial between-study heterogeneity, threshold variability, and partial verification bias affecting specificity, the pooled diagnostic estimates should be interpreted as preliminary and require confirmation in prospective studies with standardized cut-offs and uniform histopathological reference standards. Further large-scale prospective studies are warranted. https://www.crd.york.ac.uk/prospero/, identifier CRD420251233710.
Clinical relevance
In patients with thyroid cancer, what is the diagnostic accuracy of the Systemic Immune-Inflammation Index (SII) for detecting thyroid malignancy, and is SII significantly elevated in patients with lymph node metastasis compared to those without? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis (diagnostic meta-analysis using bivariate Reitsma model; association analysis using inverse-variance random-effects model)","setting":"Multi-database literature synthesis (PubMed, Scopus, Web of Science); PROSPERO-registered (CRD420251233710); institution types and geographic distribution of included studies not reported in abstract","sampleSize":"10 studies total; diagnostic sub-analysis: n=2,209 (6 studies); LNM association sub-analysis: n=2,073 (5 studies)","population":"Patients with confirmed or suspected thyroid cancer evaluated for diagnostic discrimination (malignant vs. benign thyroid disease) and/or lymph node metastasis status; specific histologic subtypes, disease stages, and demographic details of included study populations not reported in abstract","intervention":"Systemic Immune-Inflammation Index (SII), a composite hematologic biomarker calculated as (neutrophil count × platelet count) / lymphocyte count, derived from routine complete blood count","comparator":"Diagnostic sub-analysis: benign thyroid disease or absence of malignancy; LNM sub-analysis: thyroid cancer patients without lymph node metastasis","primaryOutcome":"Diagnostic sub-analysis: pooled sensitivity, specificity, likelihood ratios, and AUC of the SROC curve for SII in detecting thyroid cancer. LNM association sub-analysis: pooled mean difference (MD) in SII values between patients with and without lymph node metastasis","followUp":"Not reported (cross-sectional or perioperative measurements implied by biomarker context; longitudinal follow-up not applicable)","fundingSource":"Not reported"}
Key findings
In the diagnostic meta-analysis (6 studies; n=2,209), the SII yielded a pooled sensitivity of 76.8% (95% CI: 63.8–86.1%) and a pooled specificity of 71.2% (95% CI: 54.9–83.4%) for detecting thyroid cancer. The AUC of the summary receiver operating characteristic (SROC) curve was 0.805, indicating moderate overall discriminatory ability. The positive likelihood ratio (LR+) was 2.78 and the negative likelihood ratio (LR−) was 0.34; these values indicate modest ability to shift pre-test probability — a LR+ of 2.78 produces only a small-to-moderate increase in post-test probability, and a LR− of 0.34 does not sufficiently exclude malignancy as a standalone test. NNT and NNH are not calculable from the reported data. In the lymph node metastasis (LNM) association meta-analysis (5 studies; n=2,073), SII was significantly higher in patients with LNM compared to those without (pooled MD = 102.87; 95% CI: 58.86–146.89; p < 0.00001; I² = 56%), indicating moderate heterogeneity. Sensitivity analysis excluding one outlier study yielded consistent results with reduced heterogeneity (MD = 105.72; I² = 32%). Leave-one-out sensitivity analyses confirmed robustness of findings in both sub-analyses. The clinical magnitude of a mean SII difference of approximately 103 units is contextually dependent on the absolute SII scale and institutional reference ranges; the abstract does not report the absolute mean SII values for each group, precluding direct clinical interpretation of the effect size. No adverse event or safety data are applicable to this biomarker study.
Practice implications
This meta-analysis establishes that SII demonstrates moderate — not high — diagnostic accuracy for thyroid cancer (AUC 0.805, sensitivity 77%, specificity 71%), with wide confidence intervals around both sensitivity and specificity suggesting meaningful between-study variability. These performance metrics are substantially below the thresholds generally required for a standalone clinical diagnostic test and are inferior to established approaches such as ultrasound with fine-needle aspiration cytology. The study also establishes a statistically significant association between elevated SII and the presence of lymph node metastasis, though the mean difference of ~103 units represents an association rather than a validated predictive threshold. What the study did NOT establish: (1) optimal SII cutoff values suitable for clinical implementation, as thresholds varied across included studies; (2) whether SII adds independent predictive value beyond established clinical and pathologic risk factors (e.g., tumor size, BRAF mutation, extrathyroidal extension); (3) performance characteristics stratified by thyroid cancer histologic subtype (papillary vs. follicular vs. other); (4) prospective or longitudinal validation; (5) generalizability outside the populations studied, which likely skew toward papillary thyroid carcinoma from predominantly East Asian cohorts based on the broader SII-thyroid cancer literature. The moderate I² of 56% in the LNM analysis signals clinically relevant heterogeneity that limits pooled estimate reliability. Patients with non-papillary subtypes, those on medications affecting blood counts, or those with comorbidities affecting inflammatory indices (e.g., infection, autoimmune disease, hematologic disorders) were likely not adequately represented or controlled for. Practice should not change on the basis of this evidence alone; SII may be considered as an exploratory adjunctive variable in future prospective risk stratification tools but cannot currently be recommended as a diagnostic or staging instrument. Only abstract data were available for synthesis; full-text review may reveal additional methodological details, subgroup data, and risk-of-bias assessments that could materially affect interpretation. __LIMITATIONS__ 1. Small number of included studies (6 for diagnostic analysis, 5 for LNM analysis) limits the statistical power of pooled estimates and meta-regression. 2. Moderate-to-substantial heterogeneity (I² = 56% for LNM analysis) with wide confidence intervals around sensitivity (63.8–86.1%) and specificity (54.9–83.4%) undermines reliability of pooled diagnostic parameters. 3. SII cutoff thresholds varied across studies, making clinical implementation of a specific decision threshold impossible from current data. 4. The LNM association is expressed as a mean difference in a continuous score, not as a diagnostic accuracy metric; no sensitivity/specificity for LNM prediction is reported. 5. Likely predominance of papillary thyroid carcinoma and East Asian patient populations in source studies limits generalizability to other histologic subtypes and ethnic populations. 6. Retrospective design of most included studies introduces selection bias and limits confounding control; comorbidities and concomitant medications affecting blood counts are unlikely to have been systematically excluded. 7. Absence of direct comparison to established diagnostic modalities (US, FNA cytology, molecular markers) prevents assessment of incremental clinical value. 8. Publication bias assessment methodology not described in the abstract; small-study effects cannot be excluded. 9. Funding sources not reported; potential conflicts of interest cannot be assessed. 10. Only abstract data were available; full methodological details, QUADAS-2 risk-of-bias ratings, and subgroup analyses were not accessible for this summary. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ SII demonstrates only moderate diagnostic accuracy for thyroid cancer (AUC 0.805; sensitivity 77%, specificity 71%) and is statistically, though modestly, elevated in patients with lymph node metastasis — findings that position it as a potentially adjunctive but not standalone clinical biomarker. Given wide confidence intervals, heterogeneous SII cutoffs across studies, and absence of comparative data against standard diagnostic tools, SII cannot currently replace or meaningfully augment established thyroid cancer diagnostic pathways. Prospective multicenter validation with standardized cutoffs, histologic subtype stratification, and head-to-head comparison with ultrasound and molecular markers is required before clinical adoption.