[11] When confined to the epidermis, the outermost layer of the skin, the pre-invasive or in situ form of cSCC is termed Bowen's disease.

[2] Additional risk factors include prior scars, chronic wounds, actinic keratosis, lighter skin susceptible to sunburn, Bowen's disease, exposure to arsenic, radiation therapy, tobacco smoking, poor immune system function, previous basal cell carcinoma, and HPV infection.

[2][3] Research, both in vivo and in vitro, indicates a crucial role for the upregulation of FGFR2, part of the fibroblast growth factor receptor immunoglobin family, in cSCC cell progression.

[20] Mutations in the TPL2 gene leads to overexpression of FGFR2, which activates the mTORC1 and AKT pathways in primary and metastatic cSCC cell lines.

Utilization of a "pan FGFR inhibitor" has shown to reduce cell migration and proliferation in cSCC in vitro studies.

[5][6] Surgical removal is the typical treatment method,[2] employing simple excision for minor cases or Mohs surgery for more extensive instances.

[2] While prognosis remains favorable in the absence of metastasis, upon distant spread the five-year survival rate is markedly reduced to ~34%.

cSCC usually occurs on portions of the body commonly exposed to the sun; the face, ears, neck, hands, or arms.

[39] Genetically, cSCC tumors harbor high frequencies of NOTCH and p53 mutations as well as less frequent alterations in histone acetyltransferase EP300, subunit of the SWI/SNF chromatin remodeling complex PBRM1, DNA-repair deubiquitinase USP28, and NF-κB signaling regulator CHUK.

[41] People who have received solid organ transplants are at a significantly increased risk of developing squamous-cell carcinoma due to the use of chronic immunosuppressive medication.

[42] While the risk of developing all skin cancers increases with these medications, this effect is particularly severe for cSCC, with hazard ratios as high as 250 being reported, versus 40 for basal cell carcinoma.

[44] Heart and lung transplant recipients are at the highest risk of developing cSCC due to more intensive immunosuppressive medications used.

[45] Cutaneous squamous-cell carcinoma in individuals on immunotherapy or who have lymphoproliferative disorders (e.g. leukemia) tend to be much more aggressive, regardless of their location.

The atypia spans the full thickness of the epidermis, with the keratinocytes demonstrating intense mitotic activity, pleomorphism, and greatly enlarged nuclei.

The infiltrate can be somewhat difficult to detect in the early stages of invasion: however, additional indicators such as full thickness epidermal atypia and the involvement of hair follicles can be used to facilitate the diagnosis.

[12] Appropriate sun-protective clothing, use of broad-spectrum (UVA/UVB) sunscreen with at least SPF 50, and avoidance of intense sun exposure may prevent skin cancer.

[51] A 2016 review of sunscreen for preventing cutaneous squamous-cell carcinoma found insufficient evidence to demonstrate whether it was effective.

As a non-invasive option brachytherapy serves a painless possibility to treat in particular but not only difficult to operate areas like the earlobes or genitals.

In areas where cSCC is known to be non-aggressive, and where the patient is not immunosuppressed, EDC[clarification needed] can be performed with good to adequate cure rate.

[59] Treatment options for cSCC in situ (Bowen's disease) include photodynamic therapy with 5-aminolevulinic acid, cryotherapy, topical 5-fluorouracil or imiquimod, and excision.

[13] High-risk squamous-cell carcinoma, as defined by that occurring around the eye, ear, or nose, is of large size, is poorly differentiated, and grows rapidly, requires more aggressive, multidisciplinary management.

[63] Squamous-cell carcinoma occurring in immunosuppressed people (such as those with organ transplant, human immunodeficiency virus infection, or chronic lymphocytic leukemia) the risk of developing cSCC and having metastasis is much higher than the general population.

[64] One study found squamous-cell carcinoma of the penis had a much greater rate of mortality than some other forms of squamous-cell carcinoma, that is, about 23%,[65] although this relatively high mortality rate may be associated with possibly latent diagnosis of the disease due to patients avoiding genital exams until the symptoms are debilitating, or refusal to submit to a possibly scarring operation upon the genitalia.

This is theorized to be due to several factors; including an aging population, a greater incidence of those who are immunocompromised and the increasing use of tanning beds.

[68] Solid organ transplant recipients (heart, lung, liver, pancreas, among others) are also at a heightened risk of developing aggressive, high-risk cSCC.