Prolactin-Linked Plasma Cell-Macrophage Immune Phenotype in Synchronous Bilateral Plasma Cell Mastitis: A Two-Center Prediction Study with Tissue Correspondence.

BACKGROUND

Plasma cell mastitis (PCM) is a chronic inflammatory breast disease characterized histologically by periductal plasma cell-rich infiltration and ductal ectasia. Bilateral involvement occurs in approximately one fifth of patients, but whether synchronous bilateral PCM reflects more extensive local disease or a systemic immunoendocrine phenotype remains unclear.

OBJECTIVE

To examine whether synchronous bilateral PCM is associated with a prolactin (PRL)-centered circulating immune profile that corresponds to local tissue immune features, and to develop a combined biomarker model for identifying bilateral involvement.

METHODS

This TRIPOD-compliant retrospective study included 300 H&E confirmed PCM patients from Center A for model development and internal testing, and 40 patients from Center B for external assessment. Candidate predictors were screened using LASSO and further refined by multivariable logistic regression. Five machine learning algorithms were compared using the final predictor set. CD38, CD138, and CD68 immunohistochemistry was performed in the internal cohort to assess tissue immune features.

RESULTS

The final five-variable signature included disease course, recurrence status, PRL, AISI, and TNF-α. Among the five algorithms, GBM showed the highest discrimination, with AUCs of 0.838 in the internal test set and 0.805 in the external cohort. SHAP analysis identified PRL as the largest contributor to the GBM model and showed a non-linear contribution pattern. Removing PRL reduced AUC across all models and cohorts. Bilateral PCM showed higher CD38, CD138, and CD68 immunohistochemical scores than unilateral PCM. Serum PRL correlated moderately with all three tissue markers, whereas comparable correlations were not evident for TNF-α or CRP.

CONCLUSION

Synchronous bilateral PCM was associated with a PRL-linked dual-arm immune pattern, characterized by circulating immunoendocrine signals and local enrichment of plasma cells and macrophages. These findings suggest that bilateral PCM may represent a systemic immune phenotype rather than only wider local disease. Prospective validation and mechanistic studies are needed.