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Diagnosis & Discussion


Metaplastic breast carcinoma


The morphology and immunophenotype of this unusual malignant neoplasm is most consistent with a high-grade metaplastic carcinoma (MpBC) with myoepithelial differentiation. Unlike ductal and lobular breast carcinomas, metaplastic breast carcinoma  is characterized by the presence of two distinct cell types: epithelial and mesenchymal.[1] Although rare, accounting for only 0.2-1% of all breast cancers, MpBC portends a poor prognosis with a high mortality rate.[2] It is characterized by a higher risk of local and distant recurrence with shorter disease-free survival (DFS) and overall survival (OS) rates.[1,2] Clinically, MpBC typically presents as a large, palpable breast mass (between 2 and 5 cm on average) with ill-defined borders on imaging.[2] They are generally categorized as triple-negative breast cancers (TNBCs) because they fail to express receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2).[1]

As metaplasia is denoted as the replacement of one cell type for another more suitable cell type, MpBCs are characterized by the conversion of glandular to non-glandular epithelium.[1] Although other theories exist to explain the biphasic nature of these tumors, evidence for this metaplastic theory includes the expression of cytokeratin, S-100, and vimentin in both cell types.[1] MpBCs exhibit significant intra-tumoral heterogeneity and are comprised of squamous as well as sarcomatous components, including chondroid, osseous, and spindle cells.[1,2] According to the WHO, the subtypes of MpBC include adenosquamous carcinoma, pure squamous cell carcinoma, pure spindle cell carcinoma, fibromatosis-like metaplastic carcinoma, metaplastic carcinoma with mesenchymal differentiation (including chondroid, osseous, rhabdomyoid, neuroglial, and mixed), and finally mixed metaplastic carcinoma.[2] Song and colleagues (2013) described the clinical utility of classifying MpBC, noting that adenocarcinoma with spindle cell differentiation had the poorest 5-year OS rate (40%).[3]

Although the majority of MpBCs are TNBCs, they hold a poorer prognosis than triple-negative invasive ductal carcinomas.[2] Additionally, molecular characteristics between both malignancies differ. For instance, while triple-negative invasive ductal carcinomas have a low rate of PIK3CA mutations, the low-grade adenosquamous variant of MpBC exhibits high rates of PIK3CA mutations.[1,4] Likewise, MpBCs with osteoid or chondroid elements displayed increased Snail, BCL-2-like-1 protein, and Akt1 pathway activity when compared to non-mesenchymal MpBCs.[1,5] More recently, the molecular alterations and genetic aberrations underlying MpBCs have been elucidated. These include: epithelial-to-mesenchymal transition (EMT), overexpression of EGFR, aberrations in PIK3CA and PTEN, RPL39A14V mutations and associated enhanced nitric oxide (NO) activity, alterations in the Wnt/β-catenin pathway, enhanced variability in PD-L1 expression, and finally aberrations in genes (e.g., CDK2NA, TP53) encoding cell cycle-regulating proteins.[1]

Presently, MpBC is treated according to existing TNBC guidelines despite being relatively chemo-refractory.[1] Prospective treatment options may consist of targeted therapies based on mutational analysis. Although rare, MpBCs account for significant morbidity and mortality among breast cancer patients and early diagnosis and suitable treatment options are needed to improve patient outcomes.


1.         Reddy, T.P., et al., A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations. Breast Cancer Res, 2020. 22(1): p. 121.

2.         McCart Reed, A.E., E.M. Kalaw, and S.R. Lakhani, An Update on the Molecular Pathology of Metaplastic Breast Cancer. Breast Cancer (Dove Med Press), 2021. 13: p. 161-170.

3.         Song, Y., et al., Unique clinicopathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators. World J Surg Oncol, 2013. 11: p. 129.

4.         Bataillon, G., et al., High rate of PIK3CA mutations but no TP53 mutations in low-grade adenosquamous carcinoma of the breast. Histopathology, 2018. 73(2): p. 273-283.

5.         McQuerry, J.A., et al., Pathway activity profiling of growth factor receptor network and stemness pathways differentiates metaplastic breast cancer histological subtypes. BMC Cancer, 2019. 19(1): p. 881.