What immunohistochemistry (IHC) markers are recommended for diagnosing skin squamous cell carcinoma (SCC)?

Immunohistochemistry for Skin Squamous Cell Carcinoma

For diagnosing cutaneous squamous cell carcinoma, use p63 (or preferably p40) and CK5/6 as your primary IHC panel, with p40 demonstrating superior specificity (approaching 100%) for squamous differentiation. 1, 2

Primary Diagnostic Panel

First-Line Markers

• p40 (ΔNp63 isoform) is the most specific marker for squamous differentiation, with sensitivity and specificity both reaching 100% in identifying squamous cell carcinoma. 1, 2, 3

• p63 shows high immunoreactivity (86%) in poorly differentiated squamous cell carcinomas, though it has slightly lower specificity than p40 due to occasional overlap with adenocarcinomas. 1, 2, 3

• CK5/6 demonstrates 84% sensitivity for poorly differentiated squamous cell carcinomas and serves as a reliable squamous marker. 2

• Broad-spectrum cytokeratins (pancytokeratin) should be positive to confirm epithelial/carcinomatous origin while excluding sarcomatoid lesions. 3

Practical Algorithmic Approach

When Diagnosing Well-Differentiated SCC

• Morphologic features (keratinization, intercellular bridges) are usually sufficient for diagnosis. 1
• IHC is typically unnecessary unless confirming squamous differentiation versus other carcinoma types. 1

When Diagnosing Poorly-Differentiated SCC

• Start with p40 and CK5/6 as your minimal panel to confirm squamous differentiation. 1, 2
• If p40 is unavailable, use p63, but be aware of potential cross-reactivity with some adenocarcinomas. 1, 3
• The combination of p63 positivity with cytokeratin AE-1/3 positivity was seen in 90% of spindle cell/sarcomatoid SCCs. 4

When Distinguishing SCC from Other Entities

For SCC versus Basal Cell Carcinoma:

• SCC: EMA positive (82.7%), CEA positive (34.5%), Bcl-2 negative (96.5%), CD10 negative (100%). 5
• BCC: Bcl-2 positive (100%), CD10 positive (75.8%), EMA negative (100%), CEA negative (100%). 5

For SCC versus Atypical Fibroxanthoma (spindle cell variants):

• The most effective combination is p63 plus cytokeratin AE-1/3: positivity for both was seen in 90% of sarcomatoid SCCs and 0% of atypical fibroxanthomas. 4
• CD10 alone is not useful (positive in 60% of SCCs versus 78% of AFXs). 4

For SCC versus Squamous Cell Carcinoma In Situ versus Irritated Seborrheic Keratosis:

• SCCIS: BCL-2 positive in only 14%, IMP3 positive in 23%. 6
• ISK: BCL-2 positive in 63%, IMP3 negative in 100%. 6

Additional Markers and Patterns

Cytokeratin Profile

• CK19 is expressed in 95% of squamous cell carcinomas across various sites. 7
• CK8 is expressed in 76% of cases despite being a "simple epithelial" marker. 7
• CK20 is consistently negative in squamous cell carcinomas, which helps exclude Merkel cell carcinoma (CK20 positive in 89-100% of cases). 1, 7

Negative Markers (Should Be Absent)

• TTF-1 should be negative in squamous cell carcinomas, helping distinguish from adenocarcinoma. 1
• S100, HMB45, and CD45 should be negative to exclude melanoma and lymphoma. 3

Critical Pitfalls to Avoid

• Do not rely on p63 alone when p40 is available, as p63 has suboptimal specificity due to occasional adenocarcinoma positivity. 1, 3

• Avoid confusing normal bronchial basal cells (which are p40/p63 positive) with tumor cells when examining small biopsies. 1

• Do not use extensive IHC panels that exhaust tissue needed for molecular studies; a minimal targeted panel of p40 and one cytokeratin is usually sufficient. 1, 3

• Remember that involucrin positivity (seen in 71% of SCCs) typically localizes to central tumor areas, not peripheral cells. 7