Epithelial Cancer Markers
For detecting epithelial-derived cancers, use CAM5.2 (anticytokeratin antibody) and epithelial membrane antigen (EMA) as your primary immunohistochemical markers, as these are positive in virtually all carcinomas. 1
Primary Immunohistochemical Markers for Epithelial Cancers
Broad-Spectrum Epithelial Markers
- CAM5.2 (anticytokeratin antibody): Positive in carcinomas 1
- Epithelial membrane antigen (EMA): Positive in carcinomas 1
These two markers serve as the foundation for confirming epithelial differentiation and should be your first-line immunohistochemical tests when evaluating a poorly differentiated tumor of unknown origin.
Cytokeratin Subtyping for Tissue Origin
Once epithelial differentiation is confirmed, use CK7 and CK20 as the most important immunostains to narrow down the primary site 1:
CK7-positive/CK20-negative pattern indicates:
- Lung
- Breast
- Thyroid
- Pancreas
- Ovary
- Endometrium
- Gastric (some)
- Urothelial (some)
- Endocervical
CK7-negative/CK20-positive pattern indicates:
- Colorectal
- Gastric (some)
- Merkel cell carcinoma
CK7-negative/CK20-negative pattern indicates:
- Prostate carcinoma
CK5/6 positivity (84% sensitivity):
- Poorly differentiated squamous cell carcinoma
- Urothelial carcinoma (35%)
- Mesothelioma (all cases) 1
Site-Specific Markers
For lung primary:
- TTF-1 (thyroid transcription factor-1): Positive in most lung and thyroid carcinomas 1
For breast primary:
For thyroid primary:
- Thyroglobulin: Very specific for papillary and follicular thyroid carcinoma 1
For urothelial primary:
- Uroplakin III: 60% sensitivity in primary, 50% in metastatic urothelial carcinomas 1
- p63: Positive in 70-95% of urothelial carcinomas 1
For ovarian serous carcinoma:
- WT1: Positive in almost all ovarian serous carcinomas, including high-grade forms 1
- CA125 (serum): Elevated in 85% of advanced ovarian cancer, but only 50% of stage I disease 3, 4
For squamous cell carcinoma:
- p63: 86% sensitivity for poorly differentiated SCC 1
- CK5/6: 84% sensitivity for poorly differentiated SCC 1
Serum Tumor Markers
Gastrointestinal Cancers
- Carcinoembryonic antigen (CEA): Useful for gastrointestinal adenocarcinomas, endocervical cancer, and some lung tumors 1
- CA19-9: When combined with CEA, helps differentiate ovarian from gastrointestinal primary (high CA125/CEA ratio favors ovarian) 3
Ovarian Cancer
- CA125: Primary serum marker; elevated in 85% of advanced disease 3, 4
- CA125 combined with CEA and CA153: Detects 99.4% of epithelial ovarian cancers 5
Breast Cancer
Prostate Cancer
- PSA (prostate-specific antigen): In men with blastic bone metastases and adenocarcinoma 1
Critical Pitfalls to Avoid
Do not rely on a single marker. No immunohistochemical marker is uniformly specific or sensitive 1. Always use panels of markers tailored to the clinical and morphologic differential diagnosis.
Avoid extensive marker panels. Because markers are not uniformly specific or sensitive, performing large series of marker studies should be avoided 1. Communication with the pathologist is essential to select appropriate targeted panels.
Consider non-epithelial mimics:
- S-100 positivity suggests melanoma, not carcinoma 1
- CD45 (LCA) positivity indicates hematolymphoid malignancy 1
- Mesotheliomas can be keratin-positive; use calretinin, WT1, CK5/6, and D2-40 to distinguish 6
Serum marker limitations:
- CA125 has only 50% sensitivity in stage I ovarian cancer 3, 4
- CA15-3 should not be used for breast cancer screening due to low sensitivity 2
- False positives occur with benign conditions (endometriosis, pregnancy, cirrhosis) 3, 2
Algorithmic Approach
- Confirm epithelial differentiation: CAM5.2 and EMA
- Determine CK7/CK20 pattern: Narrows organ system
- Apply site-specific markers based on CK7/CK20 pattern and clinical presentation
- Correlate with serum markers when appropriate for the suspected primary site
- Use molecular profiling (gene expression profiling assays) if immunohistochemistry is inconclusive—these identify tissue of origin in 61-78% of cases 1