[Malignant phyllodes tumor of the breast with distant metastasis: a clinicopathological and molecular genetic analysis of ten cases].

Abstract

Objective: To investigate the clinicopathological characteristics, immunophenotypic profile, and molecular genetic changes of malignant phyllodes tumors of the breast with distant metastasis, to assess key diagnostic considerations and prognostic determinants, and to validate the utility of the 6th edition WHO classification criteria in these cases. Methods: A retrospective analysis was conducted on 10 cases of metastatic malignant phyllodes tumors of the breast diagnosed at Changzhou First People's Hospital (9 cases) and the Second Hospital of Tianjin Medical University (1 case) from January 2002 to December 2025. The clinicopathological features were summarized. Immunohistochemistry and next-generation sequencing were employed to examine the histological changes, immunophenotype, and genomic mutation spectrum. Results: All the 10 patients were female, with an age of 47.5 (44.0, 58.0) years. The mean tumor diameter was 8.5 (7.0, 10.5) cm. Among the 10 cases of malignant phyllodes tumor, 8 met all five criteria of the 5th edition WHO classification of breast tumors, while the remaining 2 fulfilled four of the five criteria. Immunohistochemical staining revealed that CKpan, CK7, CD34, and GATA3 were all negative, while p63 showed focal positive expression (3/10), and TRPS1 demonstrated moderate to strong diffuse positivity (10/10). The most frequently altered genes included TP53 (6/8), MED12 (6/8), MUC16 (6/8), FAT1 (4/8), TERT promoter (3/8), ATM (3/8), GRIN2A (3/8), PIK3CA (3/8), FAT4 (3/8), DNMT3A (3/8), KMT2C (3/8), EGFR (2/8), SETD2 (2/8), APC (2/8), and NOTCH1 (2/8). Signaling pathway enrichment analysis revealed that the commonly involved pathways included RTK/RAS (8/8), TP53 (6/8), Cell Cycle (6/8), HIPPO (5/8), MYC (4/8), NOTCH (3/8), PI3K/AKT (3/8), WNT (3/8), and TGF-β (2/8). The time to progression in the 10 cases was 18 (9, 39) months. Eight patients died of distant metastasis, with an overall survival time of 34.5 (22.0, 55.0) months. Conclusions: Malignant phyllodes tumor of the breast with distant metastasis carries an extremely poor clinical prognosis. Its diagnosis and differential diagnosis rely on integrated application of morphological features and immunophenotypic combinations. At the molecular level, it is characterized by frequent mutations in TP53, MED12, MUC16, and FAT1, and the concurrent dysregulation of RTK/RAS, TP53, and cell cycle signaling pathways may constitute the key drivers of malignant progression. The simplified criterion of "meeting four of five criteria" adopted in the 6th edition of the WHO classification significantly enhances the practical applicability of diagnosis, increases the sensitivity for detecting high-risk cases, and therefore reduces the risk of missed diagnosis.