Background: Parathyroid carcinoma is a rare malignancy, often challenging to diagnose preoperatively due to its clinical and radiological similarities to benign parathyroid adenomas. The ">3 + >3 Rule” comprises two criteria—serum calcium >3.0 mmol/L and parathyroid lesion size >3.0 cm— first described by Schulte et al. In the original study, it was posited that only 5% of parathyroid carcinomas lacked both characteristics, yielding a sensitivity of 64% and specificity of 95%. However, the accuracy of this rule remains unclear.

Objective: This systematic review aims to evaluate the diagnostic accuracy of the ">3 + >3 Rule" in identifying parathyroid carcinoma across published literature.

Methods: A systematic review was conducted across Scopus, including MEDLINE and Embase databases, for English articles on parathyroid carcinomas and adenomas. Expert opinion manuscripts, letters to the editor, commentaries, conference papers, animal studies, reviews and meta-analyses were excluded. Study selection was performed independently and in parallel by two reviewers. Title and abstract were reviewed for relevance, followed by full-text assessment.

Results: Initial search identified 10,023 studies, of which 119 met the inclusion criteria for detailed analysis. The studies involved 114 patients with parathyroid carcinoma, and 106 patients with parathyroid adenoma.  Pooled analysis revealed a sensitivity of 37.7% (95% CI 0.288-0.473), and a specificity of 59.4% (95% CI 0.495-0.688). The PPV and NPV were calculated as 50.0% (95% CI 0.418-0.582) and 47.0% (95% CI 0.418-0.523) respectively. The overall diagnostic odds ratio was 0.887 (95% CI 0.514-1.53), suggesting that this rule is limited in distinguishing parathyroid carcinoma from parathyroid adenoma. 

Conclusion: The ">3+>3 Rule" demonstrated promising clinical utility in the original study but our review debunks it and shows that many outliers exist. Further studies are warranted to validate these findings and establish a reliable clinical diagnostic criteria for parathyroid carcinoma.