Pathophysiology Malignant transformation of normal epidermal keratinocytes is the hallmark of cutaneous squamous cell carcinoma (SCC).

Some cases of SCC occur de novo (ie, in the absence of a precursor lesion); however, some SCCs arise from sun-induced precancerous lesions known as actinic keratoses, as well as leukoplakia, radiation keratosis or dermatitis, scars, chronic ulcers, or chronic sinusitis. People with actinic keratosis have atypical squamous cells in one third to one half of the epidermis, and those with multiple actinic keratoses are at increased risk for developing SCC. [5] Those with Bowen disease (see the following image), or SCC in situ, have atypical keratinocytes in the entire epidermis. SCC is capable of locally infiltrative growth, spread to regional lymph nodes, and distant metastasis, most often to the lungs. Invasive SCC involves the epidermis and invades the dermis.

Squamous cell carcinoma in situ (Bowen disease). Courtesy of Hon Pak, MD. One critical pathogenic event is the development of apoptotic resistance through functional loss of TP53, a well-studied tumor suppressor gene. Ultraviolet (UV) Binduced photocarcinogenesis appears to work by suppressing the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage, specifically the generation of pyrimidine dimers in keratinocyte DNA that is a molecular trigger of UV-mediated immunosuppression.[6] This process is known to result in genetic mutation of TP53. TP53 mutations are seen in over 90% of skin cancers diagnosed in the United States, as well as most precursor skin lesions, suggesting that loss of TP53 is an early event in the development of cutaneous SCC.[7, 8] Upon subsequent UV radiation exposure, keratinocytes undergo clonal expansion, acquiring further genetic defects, and ultimately leading to invasive cutaneous SCC. Other tumor suppressor genes found to be mutated in SCC include P16(INK4a) and P14 (ARF).[9] Many other genetic abnormalities are believed to contribute to the pathogenesis of cutaneous SCC, including mutations of BCL2 and RAS. Likewise, alterations in intracellular signal transduction pathways, including epidermal growth factor receptor (EGFR) and cyclooxygenase (COX), have been shown to play a role in the development of cutaneous SCC. Salehi et al noted that translational control is critical for the proper regulation of the cell cycle, tissue induction, and growth.[2] The eukaryotic initiation factor 4E (eIF4E) is important for these processes and may play an important role in SCC. [2]Although typically observed in elderly patients, SCC may be seen in younger patients with a

history of radiotherapy or in patients with human immunodeficiency virus (HIV) infection (see the image below). Human papillomavirus (HPV) infectionor TP53 overexpression may play a role in development of SCC in patients who are infected with HIV.[10, 11] Multiple infectious agents likely play a role in the development of SCC of the conjunctiva via the actions of infectious oncogenes and chronic antigenic stimulation.[12]

A 35-year-old man who is positive with human immunodeficiency virus (HIV) infection presented with a 2-year history of a slowly enlarging, left lower eyelid lesion; incisional biopsy revealed squamous cell carcinoma. Occupations with considerable exposure to oils or tar may be associated with increased incidence of SCC of eyelids. In patients with xeroderma pigmentosum, defective DNA repair causes predisposition for development of malignant epithelial lesions, including SCC