An Update on the Molecular Pathology of Metaplastic Breast Cancer

Abstract

Metaplastic breast cancer (MpBC) is a fascinating morphologic sub-type of breast cancer, characterised by intra-tumoural heterogeneity. By definition, these tumors show regions of metaplasia that can present as spindle, squamous, chondroid or even osseous differentiation. MpBC are typically triple-negative, and are therefore not targetable with hormone therapy or anti-HER2 therapies, leaving only chemotherapeutics for management. MpBC are known for their aggressive course and poor response to chemotherapy. We review herein the pathology and molecular landscape of MpBC and discuss opportunities for targetted therapies as well as immunotherapies.

Presentation and treatment of aggressive, Triple‐Negative carcinosarcoma of the breast

“… 17 According to WHO guidelines, MpBCs are classified as spindle cell, squamous cell, matrix‐producing, carcinosarcoma, or osteoblastic, 18 although they can be further described according to unique histotype. 5 , 15 , 17 , 19 A biphasic MpBC, carcinosarcoma contains both epithelial and sarcomatous components, 15 indicated by co‐expression of epithelial indicators like AE‐1/3, and mesenchymal indicators like vimentin and SMA. 17 Differential histological diagnoses of MpBC include myoepithelial carcinoma, myofibroblastic tumors, malignant phyllodes tumors, pleomorphic adenoma, and adenomyoepithelioma.…”

“… 11 This treatment paradigm, however, contradicts growing evidence that MpBC is a distinct molecular entity. 23 MpBCs have a high incidence of a triple‐negative (TN) phenotype, 15 lacking receptors for estrogen, progesterone, and HER2, 12 , 23 , 24 , 25 limiting targeted treatment options. 11 One retrospective analysis by Xuexin et al concluded that in TN MpBC patients, chemotherapy was not associated with improved survival.…”

“…The carcinosarcoma exhibited by the patient falls into a larger umbrella category of metaplastic breast carcinomas (MpBCs), 15 a rare type of neoplasm accounting for 0.5%–3% of mammary carcinomas 17 . According to WHO guidelines, MpBCs are classified as spindle cell, squamous cell, matrix‐producing, carcinosarcoma, or osteoblastic, 18 although they can be further described according to unique histotype 5,15,17,19 . A biphasic MpBC, carcinosarcoma contains both epithelial and sarcomatous components, 15 indicated by co‐expression of epithelial indicators like AE‐1/3, and mesenchymal indicators like vimentin and SMA 17 .…”

“…In the breast, carcinosarcoma accounts for less than 0.2–1% of new cases. 5 , 13 , 14 , 15 One oft‐cited study of this malignancy demonstrated a cumulative 5‐year survival rate of 49%, with a precipitous decrease in survival odds at later stages of the disease. Lacking a treatment standard, 5 options for remedying breast carcinosarcoma include surgical resection, chemotherapy, and radiation, 1 , 16 although recurrence of disease has been known to occur in these approaches toward treatment.…”

Case Report: Analysis of Plasma Extracellular Vesicles in a Triple Negative Spindle-Cell Metaplastic Breast Cancer Patient

“…It is a triple negative ductal carcinoma that shows intra-tumoural heterogeneity that has epithelial differentiation into squamous and/or mesenchymal elements, with often co-existing cells that display a spindle, squamous, chondroid or osseous transformation ( 1 ). The World Health Organization Classification groups MpBCs in different subtypes depending on the metaplastic features ( 2 – 5 ): squamous cell, fibromatosis-like metaplastic, low grade adenosquamous, spindle cell, metaplastic with mesenchymal differentiation, mixed metaplastic, and myoepithelial carcinomas, all similarly treated ineffectually in the clinical setting. Indeed, MpBCs do not respond to hormone and anti-HER2 therapies, and to conventional chemotherapies, generating the worst prognosis among breast cancer types.…”