Genetic Profiling of Mammary Periductal Stromal Tumors With Histologic Correlation Highlights High-Grade and Low-Grade Groups and Similarities to Phyllodes Tumors

Abstract

Periductal stromal tumors (PDST) of the breast are rare biphasic neoplasms with morphologic similarities to phyllodes tumors (PTs). The histologic spectrum of PDST is broad but has not been well characterized, and its genetic underpinnings remain unknown. We profiled PDST by targeted next-generation sequencing in correlation with their histomorphology, immunophenotype, and clinical characteristics (n = 15). All patients were female, including 2 with Li-Fraumeni syndrome (LFS), with a mean age of 48 years. Forty-two percent had synchronous or metachronous PT and/or fibroadenoma. Most PDST expressed CD34 (15/15), smooth muscle actin (12/14), and at least focal nuclear HMGA2 (8/12) and/or beta-catenin (6/12). High-grade PDST (HGPDST, n = 8) were defined by marked nuclear pleomorphism (8/8), and most had high (≥10 mitoses/10 high-power field) and/or atypical mitotic activity (7/8) and pleomorphic multinucleated tumor cells (7/8). All HGPDST had p53 (88%, 7/8) and/or Rb/CDKN2A (75%, 6/8) alterations by next-generation sequencing or immunohistochemistry. p53 Aberrations correlated with the presence of pleomorphic multinucleated tumor cells. Both patients with LFS had HGPDST with loss of heterozygosity of the germline TP53 variant. Other altered genes in HGPDST included EGFR (25%, 2/8), NF1 (25%, 2/8), TERT promoter, PIK3CA, CDKN2A/B, LZTR1, KMT2B, and ARID2 (1 case each). Low-grade PDST, which lacked marked pleomorphism, high mitotic activity, or atypical mitoses (n = 7), had simpler genomes than HGPDST and lacked bona fide cancer gene alterations, with TERT promoter mutation in 1 case. Copy number alterations in PDST overlapped with those reported in PT, including 13q loss in all HGPDST. Copy number profiling revealed shared clonality of synchronous low-grade PDST and PT in 1 patient. In summary, we describe herein the genetic landscape of PDST, demonstrate correlation of genetic features with high-grade vs low-grade histology, and identify TP53 among key oncogenic drivers of HGPDST, including in LFS. The genetics of HGPDST overlap with borderline or malignant PT, consistent with their classification as PT variants that arise through a MED12-independent pathway.

Keywords: Li-Fraumeni; TERT; fibroepithelial; p53; periductal stromal tumor; phyllodes tumor.