cutaneous squamous-cell carcinoma cutaneous squamous-cell carcinoma cutaneous squamous-cell carcinoma (cscc), or squamous-cell carcinoma of the skin, also known as squamous-cell skin cancer, is one of the main types of skin cancer along with basal-cell carcinoma and melanoma. it usually presents as a hard lump with a scaly top but can also form an ulcer. onset is often over months. cutaneous squamous-cell carcinoma is more likely to spread to distant areas than basal cell cancer. when confined to the outermost layer of the skin, a precancerous or in situ form of cscc is known as bowen's disease. cutaneous squamous-cell carcinomaother namessquamous-cell carcinoma of the skin, squamous-cell skin cancer, epidermoid carcinoma, squamous-cell epithelioma of the skincutaneous squamous-cell carcinoma tends to arise from actinic keratoses (premalignant lesions); surface is usually scaly and often ulcerates (as shown here).specialtydermatology, plastic surgery, otorhinolaryngologysymptomshard lump with a scaly top or ulceration.risk factorsultraviolet radiation, actinic keratosis, tobacco smoking, lighter skin, arsenic exposure, radiotherapy, poor immune system function, hpv infectiondiagnostic methodtissue biopsydifferential diagnosiskeratoacanthoma, actinic keratosis, melanoma, warts, basal cell cancerpreventiondecreased uv radiation exposure, sunscreentreatmentsurgical removal, radiotherapy, chemotherapy, immunotherapyprognosisusually goodfrequency2.2 million (2015)deaths51,900 (2015) the greatest risk factor is high total exposure to ultraviolet radiation from the sun. other risks include prior scars, chronic wounds, actinic keratosis, lighter skin, bowen's disease, arsenic exposure, radiation therapy, tobacco smoking, poor immune system function, previous basal cell carcinoma, and hpv infection. risk from uv radiation is related to total exposure, rather than early exposure. tanning beds are becoming another common source of ultraviolet radiation. risk is also elevated in certain genetic skin disorders, such as xeroderma pigmentosum and certain forms of epidermolysis bullosa. it begins from squamous cells found within the skin. diagnosis is often based on skin examination and confirmed by tissue biopsy. new in vivo and in vitro studies have proven that the upregulation of fgfr2, a subset of the fibroblast growth factor receptor (fgfr) immunoglobin family, has a critical role to play in the progression of cscc cells. mutation in the tpl2 gene causes overexpression of fgfr2, which activates mtorc1 and akt pathways in both primary and metastatic cscc cell lines. only by using fgfr pan-inhibitor, azd4547, could cell migration and cell proliferation on cscc be attenuated additionally, research has identified common driver mutations in cscc, with alterations in the notch and p53 pathways occurring at high frequency and mutations in the hippo and ras/mapk/pi3k occurring at lower frequency decreasing exposure to ultraviolet radiation and the use of sunscreen appear to be effective methods of preventing cutaneous squamous-cell carcinoma. treatment is typically by surgical removal. this can be by simple excision if the cancer is small otherwise mohs surgery is generally recommended. other options may include application of cold and radiation therapy. in the cases in which distant spread has occurred chemotherapy or biologic therapy may be used. as of 2015, about 2.2 million people have cscc at any given time. it makes up about 20% of all skin cancer cases. about 12% of males and 7% of females in the united states developed cscc at some point in time. while prognosis is usually good, if distant spread occurs five-year survival is ~34%. in 2015 it resulted in about 51,900 deaths globally. the usual age at diagnosis is around 66. following the successful treatment of one case of cscc people are at high risk of developing further cases. signs and symptoms cutaneous squamous-cell carcinoma scc of the skin begins as a small nodule and as it enlarges the center becomes necrotic and sloughs and the nodule turns into an ulcer, and generally are developed from an actinic keratosis. once keratinocytes begin to grow uncontrollably, they have the potential to become cancerous and produce cutaneous squamous-cell carcinoma. the lesion caused by cscc is often asymptomatic ulcer or reddish skin plaque that is slow growing intermittent bleeding from the tumor, especially on the lip the clinical appearance is highly variable usually the tumor presents as an ulcerated lesion with hard, raised edges the tumor may be in the form of a hard plaque or a papule, often with an opalescent quality, with tiny blood vessels the tumor can lie below the level of the surrounding skin, and eventually ulcerates and invades the underlying tissue the tumor commonly presents on sun-exposed areas (e.g. back of the hand, scalp, lip, and superior surface of pinna) on the lip, the tumor forms a small ulcer, which fails to heal and bleeds intermittently evidence of chronic skin photodamage, as in multiple actinic keratoses (solar keratoses) the tumor grows relatively slowly spread unlike basal-cell carcinoma (bcc), squamous-cell carcinoma (scc) has a higher risk of metastasis. risk of metastasis is higher clinically in scc arising in scars, on the lower lips or mucosa, and occurring in immunosuppressed and solid organ transplant patients. risk of metastasis is also higher in scc that are > 2 cm in diameter, growth into the fat layer and along nerves, thickness > 6 mm. causes cutaneous squamous-cell carcinoma is the second-most common cancer of the skin (after basal-cell carcinoma, but more common than melanoma). it usually occurs in areas exposed to the sun. sunlight exposure and immunosuppression are risk factors for scc of the skin, with chronic sun exposure being the strongest environmental risk factor. there is a risk of metastasis starting more than 10 years after diagnosable appearance of squamous-cell carcinoma, but the risk is low, though much higher than with basal-cell carcinoma. squamous-cell cancers of the lip and ears have high rates of local recurrence and distant metastasis. in a recent study, it has also been shown that the deletion or severe down-regulation of a gene titled tpl2 (tumor progression locus 2) may be involved in the progression of normal keratinocytes into becoming squamous-cell carcinoma. cscc represents about 20% of the non-melanoma skin cancers, but 80-90% of those with metastatic potential are located on the head and neck. tobacco smoking also increases the risk for cutaneous squamous-cell carcinoma. the vast majority of cscc cases are those of the skin, and are often the result of ultraviolet exposure. cscc usually occurs on portions of the body commonly exposed to the sun; the face, ears, neck, hands, or arms. the main symptom is a growing bump that may have a rough, scaly surface and flat reddish patches. unlike basal-cell carcinoma, cscc carries a higher risk of metastasis and may spread to the regional lymph nodes, erythroplasia of queyrat (scc in situ of the glans or prepuce in males, m: 733 : 656 or the vulvae in females.) may be induced by human papilloma virus. it is reported to occur in the corneoscleral limbus. erythroplasia of queyrat may also occur on the anal mucosa or the oral mucosa. some sources state that this condition is synonymous with bowen's disease, however generally speaking bowen's disease refers to carcinoma in situ of any location on the skin such as the lower leg. 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. immunosuppression 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. 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. the incidence of cscc development increases with time posttransplant. heart and lung transplant recipients are at the highest risk of developing cscc due to more intensive immunosuppressive medications used. 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 risk of cscc, and non-melanoma skin cancers generally, varies with the immunosuppressive drug regimen chosen. the risk is greatest with calcineurin inhibitors like cyclosporine and tacrolimus, and least with mtor inhibitors, such as sirolimus and everolimus. the antimetabolites azathioprine and mycophenolic acid have an intermediate risk profile. diagnosis diagnosis is confirmed via biopsy of the tissue or tissues suspected to be affected by scc. for the skin, look under skin biopsy. the pathological appearance of a squamous-cell cancer varies with the depth of the biopsy. for that reason, a biopsy including the subcutaneous tissue and basilar epithelium, to the surface is necessary for correct diagnosis. the performance of a shave biopsy (see skin biopsy) might not acquire enough information for a diagnosis. an inadequate biopsy might be read as actinic keratosis with follicular involvement. a deeper biopsy down to the dermis or subcutaneous tissue might reveal the true cancer. an excision biopsy is ideal, but not practical in most cases. an incisional or punch biopsy is preferred. a shave biopsy is least ideal, especially if only the superficial portion is acquired. characteristics histopathologically, the epidermis in cscc in situ (bowen's disease) will show hyperkeratosis and parakeratosis. there will also be marked acanthosis with elongation and thickening of the rete ridges. these changes will overly keratinocytic cells which are often highly atypical and may in fact have a more unusual appearance than invasive cscc. the atypia spans the full thickness of the epidermis, with the keratinocytes demonstrating intense mitotic activity, pleomorphism, and greatly enlarged nuclei. they will also show a loss of maturity and polarity, giving the epidermis a disordered or "windblown" appearance. two types of multinucleated cells may be seen: the first will present as a multinucleated giant cell, and the second will appear as a dyskeratotic cell engulfed in the cytoplasm of a keratinocyte. occasionally, cells of the upper epidermis will undergo vacuolization, demonstrating an abundant and strongly eosinophilic cytoplasm. there may be a mild to moderate lymphohistiocytic infiltrate detected in the upper dermis. histopathology of squamous-cell carcinoma in situ (black arrow), compared to normal skin, showing marked atypia. squamous-cell carcinoma in situ, showing prominent dyskeratosis and aberrant mitoses at all levels of the epidermis, along with marked parakeratosis. in situ disease bowen's disease is essentially equivalent to and used interchangeably with cscc in situ, when not having invaded through the basement membrane. depending on source, it is classified as precancerous or cscc in situ (technically cancerous but non-invasive). in cscc in situ (bowen's disease), atypical squamous cells proliferate through the whole thickness of the epidermis. the entire tumor is confined to the epidermis and does not invade into the dermis. the cells are often highly atypical under the microscope, and may in fact look more unusual than the cells of some invasive squamous-cell carcinomas. cscc in situ, high magnification, demonstrating an intact basement membrane. cscc in situ cscc in situ cscc in situ cscc in situ erythroplasia of queyrat is a particular type of bowen's disease that can arise on the glans or prepuce in males,: 733 : 656 and the vulvae in females. it mainly occurs in uncircumcised males, over the age of 40. it is named for french dermatologist louis queyrat (1856–1933), who was head of the dermatology service of l'hôpital ricord, a venereal hospital in paris, now hôpital cochin. invasive disease in invasive cscc, tumor cells infiltrate through the basement membrane. 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. later stages of invasion are characterized by the formation of nests of atypical tumor cells in the dermis, often with a corresponding inflammatory infiltrate. gross slice of squamous-cell carcinoma of the skin superficially invasive cutaneous squamous-cell carcinoma. these lesions often do not show the marked pleomorphism and atypical nuclei of cscc in situ, but manifest early keratinocyte invasion of the dermis. high magnification demonstrates the pleomorphism of the invading keratinocytes invasive nests with characteristic large celled centers. ulceration (at left) is common in invasive cscc. degree of differentiation well-differentiated (yet invasive) cscc, showing prominent keratinization. it may form pearl-like structures where dermal nests of keratinocytes attempt to mature in a layered fashion. well-differentiated cscc has slightly enlarged hyperchromatic nuclei with abundant amounts of cytoplasm. intercellular bridges will frequently be visible. moderately differentiated lesions of invasive cscc show much less organization and maturation with significantly less keratin formation. poorly differentiated, where