Morphologic and genetic heterogeneity in breast fibroepithelial lesions-a comprehensive mapping study

Mod Pathol. 2020 Sep;33(9):1732-1745. doi: 10.1038/s41379-020-0533-0. Epub 2020 Apr 22.

Abstract

Breast fibroepithelial lesions (FELs) encompass the common fibroadenoma (FA) and relatively rare phyllodes tumour (PT); the latter entity is usually classified as benign, borderline or malignant. Intratumoural heterogeneity is frequently present in these tumours, making accurate histologic evaluation challenging. Despite their rarity, PTs are an important clinical problem due to their propensity for recurrence and, in the case of malignant PT, metastasis. Surgical excision is the mainstay of management. Recent work has uncovered myriad genetic alterations in breast FELs. In this study, exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including FAs, PTs of all grades, and a case of metaplastic spindle cell carcinoma arising in PT, in order to elucidate their intratumoural genetic repertoire. Gene mutations identified encompassed cell signalling, tumour suppressor, DNA repair and cell cycle regulating pathways. Mutations common to multiple tumour regions generally showed higher variant allele frequency. Frequent mutations included MED12, TP53, RARA and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumour progression. In summary, histological heterogeneity correlated with genetic changes in breast FELs.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Female
  • Fibroadenoma / genetics
  • Fibroadenoma / pathology*
  • Genetic Heterogeneity*
  • Humans
  • Mediator Complex / genetics
  • Middle Aged
  • Mutation*
  • Phyllodes Tumor / genetics
  • Phyllodes Tumor / pathology*
  • Retinoic Acid Receptor alpha / genetics
  • Tumor Suppressor Protein p53 / genetics

Substances

  • MED12 protein, human
  • Mediator Complex
  • RARA protein, human
  • Retinoic Acid Receptor alpha
  • Tumor Suppressor Protein p53
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human