Nonmelanoma skin cancer (NMSC) is a frequently reported neoplasm in Caucasians, with squamous-cell carcinoma (cSCC) and basal-cell carcinoma being the commonest variants. 

The immunohistochemical study of cSCC is important for diagnosing its rare forms, crucial for survival. Further, appropriate staging will not only help learn about the extent of the disease but will also facilitate suitable treatment. Additionally, tumor characteristics like its size, thickness, depth, margins, histological grade and subtype, perineural and lymphovascular invasion will help predict disease progression and disease-specific death.

Cutaneous poorly differentiated SCC can be diagnosed utilizing some immunohistochemistry (IHC) markers like p63, p40, CKMNF116 and CK34βE12 (CK903). 

Aggressive and invasive properties, as well as tumor progression risk, can be predicted by IHC markers like:

• Markers of mesenchymal-epithelial transition (E-cadherin, podoplanin and Twist)
• Markers of invasion
• Markers of vascular/lymphatic cell proliferation (CD105, DOG-1, maspin, anti-podoplanin antibodies, CD10, IGF-1R, EGFR, p300 marker and CD133)
• Inflammatory markers.

Recurrence risk can be predicted using:

• EMT markers (AXIN2 and SNAIL)
• Invasion markers (S-100, p75NGFR, INPP5A)
• Proliferation marker (Ki-67).

Metastasis risk can be predicted using:

• EMT markers (nuclear β-catenin, E-cadherin, Zeb1, podoplanin, Twist and human epidermal growth factor receptor 4)
• Invasion markers (p75NGFR, S-100, FAK and INPP5A)
• Proliferation markers (anti-podoplanin antibodies, Ki-67, EGFR, p300 marker)
• A lower density of peri-neoplastic inflammatory infiltrates in immunocompromised individuals.

The therapeutic targets are:

• Podoplanin (a marker of EMT)
• FAK (a marker of invasion)
• CD105, cytoplasm to nuclear translocation of maspin, DOG-1, IGF-1R, EGFR, CD133 (markers of proliferation)
• AIM2 (a marker of inflammation).

Knowledge regarding the molecular mechanisms causing the development and progression of cSCC; and understanding the value of IHC markers will help in discovering novel biomarkers and developing improved therapeutic strategies.