Metaplastic Carcinoma

Epidemiology:

• 0.2-5% of all invasive breast cancers, depending on the definition used by authors

Common sites:

Gross features:

• Relatively large in general, mean 3.9 cm

Histologic features:

• Squamous cell differentiation
• Mesenchymal differentiation
• Spindle cell
• Chondroid
• Osseous
• Rhabdomyoid
• Others
• May be a complex mixture of carcinoma and metaplastic areas
• Keratin expression often variable, and not uncommonly focal
• Low-grade adenosquamous carcinoma:
• Well-developed glandular and tubular formations intimately admixed with solid nests of squamous cells in a spindle-cell background
• Small glandular structures
• Rounded rather than angulated ocntours
• Solid cords of epithelial cells
• Contain squamous cells maybe
• Squamous pearls maybe
• Squamous cyst maybe
• Long, slender extensions at the periphery infiltrating between normal breast structures typically
• Clusters of lymphocytes at the periphery often (“cannon ball” pattern)
• Association has been reported with adenomyoepithelioma and sclerosing proliferative lesions
• Fibromatosis-like metaplastic carcinoma
• Bland spindle cells
• Pale eosinophilic cytoplasm
• Slender nuclei with tapered edges
• Finely distributed chromatin
• Nuclear atypia mild or absent
• Wavy, interlacing fascicles often
• Long fascicles with finger-like extensions infiltrating the adjacent breast parenchyma maybe
• Embedded in stroma
• Varying degrees of collagenization
• Cords and clusters of plump spindled and more epithelioid cells often
• Pervascular distribution often
• Gradual transition from plump cells to spindle cells frequently
• Focal squamous differentiation maybe
• P63 positive almost invariably
• Keratins positive invariably
• May be focal, or restricted to plump spindle and epithelioid cells
• Squamous cell carcinoma
• Cystic lesion usually
• Lined by squamous cells with varying degrees of nuclear atypia and pleomorphism
• Infiltration of adjacent stroma in sheets, cords, and nests with a conspicuous stromal reaction
• Inflammatory infiltrate prominent usually
• Spindle cells at the invasive front commonly
• Acantholytic variant:
• Irregular spaces lined by atypical squamous cells with a pseudoglandular or pseudoangiosarcomatous appearance
• DDx angiosarcoma
• Pure or mixed with coexisting invasive carcinoma NST
• Note: squamous differentiation can also be found in carcinomas with medullary-like features
• Primary squamous cell carcinoma from other sites esp. skin must be ruled out
• Spindle cell carcinoma
• Atypical spindle cells
• Architectural patterns range in a multitude of fashions
• Long fascicles
• Herringbone
• Interwoven
• Short fascicles
• Storiform
• Mixture most often
• Nuclear pleomorphism moderate to high usualy
• Inflammatory infiltrate often
• Areas with more epithelioid morphology or squamous differentiation can be found
• May be a spectrum from spindle squamous cell carcinoma on one hand and malignant myoepithelioma/myoepithelial carcinoma on other hand
• Metaplastic spindle cell carcinoma diagnosis can be rendered based on the presence of any evidence of epithelial differentiation by histopathological and/or immunohistochemical analysis
• Presence of DCIS at the periphery or admixed should also prompt a diagnosis
• Metaplastic carcinoma with mesenchymal differentiation
• Admixture of mesenchymal components with carcinomatous areas
• Chondroid
• Osseous
• Rhabdomyoid
• Neuroglial
• Varying degrees of atypia from minimal to frankly malignant
• Carcinomatous areas may be in form of tubules, solid clusters, and/or foci of squamous differentiation
• May require extensive sampling to find the carcinomatous areas
• Epithelial markers expressed by IHC, usually HMWK
• Mixed metaplastic carcinomas (often seen upon extensive sampling)

Immunophenotype:

Marker:	Sensitivity:	Specificity:
ER (neg)	> 90%
PR (neg)	> 90%
HER2 (neg)	> 90%
P63	> 90%	Neg in phyllodes
CK5/6		Neg in phyllodes
CK14		Neg in phyllodes
EGFR
34BE12		Neg in phyllodes
AE1/AE3		Neg in phyllodes
LMWK (commonly neg)		Neg in phyllodes
CD34 (neg)		Pos in phyllodes
Bcl2 (neg)		Pos in phyllodes

Molecular features:

• “basal-like” gene expression subtype
• “claudin-low” molecular subtype (spindle cell metaplasia or epithelial-to-mesenchymal transition)
• Complex genomes
• Similar to other types of triple-negative and basal-like breast cancers
• TP53 mutation (vast majority)
• CDKN2A loss
• PTEN loss
• PIK3CA mutation
• Wnt pathway gene mutations
• CTNNB1 mutation
• EGFR high polysomy and amplification (10-25%)
• Squamous and/or spindle cell elements

Other features:

• Clinical features similar to other ER-negative invasive ductal carcinoma NST
• Distant mets > LN mets
• Lower response rates to conventional adjuvant chemotherapy
• Worse clinical outcome than other triple neg breast cancers
• Low-grade adenosquamous carcinomas and low-grade fibromatosis-like tumours/carcinomas may have a better clinical outcome than other types of metaplastic breast cancer

References:

• WHO Classification of Tumours of the Breast (2012)