Design: Comparative IHC and NGS study with test set
Population: 15 metaplastic breast carcinomas, 18 cutaneous SCCs, 48 other SCCs, 9 uncertain cases
Primary outcome: Distinguishing IHC and molecular features
Effect: CK7 (p = 0.0005), SOX10, TRPS1 higher in breast; NOTCH1 and UV signature only in skin

The authors characterised 15 metaplastic breast carcinomas with squamous differentiation and 18 cutaneous SCCs of breast and chest skin, and compared them with 48 SCCs from other sites.

CK7, SOX10 and TRPS1 were more often expressed in metaplastic breast carcinoma (p = 0.0005, 0.023 and 0.029). HER2 overexpression occurred only in breast and oesophageal carcinomas. On sequencing, PIK3CA/PIK3R1 alterations were more frequent in breast (p = 0.004), NOTCH1 mutations were exclusive to skin, and cutaneous SCC had higher mutational burden and UV signatures. Applied to nine cases of uncertain origin, the molecular data added value.

The distinction matters because management differs completely. A stepwise approach — morphology and clinical context, then IHC, then selected molecular features — is supported.

Look for DCIS or epidermal connection first; either usually settles it.
Stain CK7, SOX10 and TRPS1 when origin is uncertain.
If still unresolved, request sequencing for PIK3CA, NOTCH1 and UV signature.
Ask the clinician about skin involvement and sun exposure.

Why it matters

Calling breast versus skin origin decides between breast oncology pathways and skin cancer surgery.

The statistics, in plain English

The p-values show the markers differ between groups, but with 15 and 18 cases the study cannot give reliable sensitivity for any single marker. Use them together, not alone.