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, generally developing 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, ears, 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, presence of lymphovascular invasion, poorly differentiated cell architecture on histology, or thickness greater than 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 with the majority of cSCC cases being located on exposed skin and often the result of ultraviolet exposure. cSCC represents about 20% of the non-melanoma skin cancers; 80-90% of cSCCs with metastatic potential are located on the head and neck. Squamous-cell cancers of the lip and ears also have high rates of local recurrence and distant metastasis. Sunlight exposure and immunosuppression are risk factors for SCC of the skin, with chronic sun exposure being the strongest environmental risk factor. Tobacco smoking also increases the risk for cutaneous squamous-cell carcinoma. SCC in situ of the glans or prepuce in males, It is reported to occur in the corneoscleral limbus. SCC may also occur on the anal mucosa or the oral mucosa. A significant proportion of cSCC and its precursor lesions carry UV-induced p53 mutations. These mutations are present in up to 90% of cSCC cases. The detection of p53 mutations in precursor lesions indicates that this could be an early event in the development of squamous cell carcinoma. Rare genetic disorders such as albinism and xeroderma pigmentosum increase the risk of SCC, typically with an earlier disease onset. 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) tends 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 skin biopsy of the tissue or tissues suspected to be affected by SCC. 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. Histological characteristics File:Histopathology of squamous cell carcinoma in situ.jpg|Histopathology of squamous-cell carcinoma in situ (black arrow), compared to normal skin, showing marked atypia. File:Micrograph of squamous cell carcinoma in situ - 100x.jpg|Squamous-cell carcinoma in situ, showing prominent dyskeratosis and aberrant mitoses at all levels of the epidermis, along with marked parakeratosis. and the vulva in females. It mainly occurs in uncircumcised males, over the age of 40. Invasive disease In invasive cSCC, tumor cells infiltrate through the basement membrane and may involve hair follicles, or form nests of atypical, cancerous cells in the dermal layer. Invasive SCC may also involve a corresponding inflammatory infiltrate. File:Gross pathology of squamous cell carcinoma.jpg|Gross slice of squamous-cell carcinoma of the skin File:Micrograph of invasive squamous cell carcinoma - 150x.jpg|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. File:Micrograph of invasive squamous cell carcinoma - 200x.jpg|High magnification demonstrates the pleomorphism of the invading keratinocytes File:Ulcer border of a squamous cell skin cancer.jpg|Invasive nests with characteristic large celled centers. Ulceration (at left) is common in invasive cSCC. Degree of differentiation File:Micrograph of well-differentiated and invasive squamous-cell carcinoma.jpg|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. File:Micrograph of moderately differentiated and invasive squamous-cell carcinoma.jpg|Moderately differentiated lesions of invasive cSCC show much less organization and maturation with significantly less keratin formation. File:Micrograph of clear-cell squamous-cell carcinoma.jpg|Poorly differentiated, where attempts at keratinization are often no longer evident. This is a clear-cell squamous-cell carcinoma. The dysplastic cells infiltrated cords through the dermis. Poorly differentiated cSCC has greatly enlarged pleomorphic nuclei showing a high degree of atypia and frequent mitoses. File:Micrograph of clear-cell squamous-cell carcinoma with focus of obvious squamous-cell features, annotated.jpg|Poorly differentiated clear-cell squamous-cell carcinoma. For this type of cSCC, immunostains will likely be required to classify it unless other areas of the tumor show obvious squamous-cell features, such as seen here (arrow). ==Prevention==

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

Most cutaneous squamous-cell carcinomas are removed with surgery. Smaller lesions which are lower risk may also be destroyed with electrodesiccation and curettage. Radiation or radiotherapy can also be a standalone option in treating cSCC in those who are not candidates for surgery. Certain forms of high risk disease including recurrent cSCC, locally advanced cancer that is not treatable with surgery, regionally invasive cancer, or cancer with distant metastasis are treated with systemic therapy. Treatment options for cSCC in situ (Bowen's disease) include photodynamic therapy with 5-aminolevulinic acid, cryotherapy, topical 5-fluorouracil or imiquimod, and excision. A meta-analysis showed evidence that PDT is more effective than cryotherapy and has better cosmetic outcomes. There is generally a lack of evidence comparing the effectiveness of all treatment options. Seventy to 80% of cSCCs recur within 2 years of treatment. Periodic skin exams are recommended after treatment. ==Prognosis==

The long-term outcome of squamous-cell carcinoma is dependent upon several factors: the subtype of the carcinoma, available treatments, location and severity, and various patient health-related variables (accompanying diseases, age, etc.). Generally, the long-term outcome is positive, with a metastasis rate of 1.9-5.2% and a mortality rate of 1.5-3.4%. Lesions that are greater than 2 mm in depth, or invading beyong the subcutaneous fat, invading local nerves or lymph nodes, having a diameter of more than 2 cm, arising from a scar, or arising from the temple, ear, or lips are associated with a greater risk of metastasis. For 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 in the general population. The risk of metastasis in those who are immunosuppressed is 7.3% in cSCC of the body, and 11% of cSCC of the head and neck. Other population based studies estimate the risk of cSCC metastasis being 2.7-5 times higher in those who are immunocompromized. ==Epidemiology==

death from melanoma and other skin cancers per 100,000 inhabitants in 2004. The incidence of cutaneous squamous-cell carcinoma continues to rise around the world. 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. Risk factors for cSCC vary with age, gender, race, geography, and genetics. The incidence of cSCC increases with age, and those 75 years or older are at a 5-to 10-fold increased risk of developing cSCC as compared with those who are younger than 55 years old. Solid organ transplant recipients (heart, lung, liver, pancreas, among others) are also at a heightened risk of developing aggressive, high-risk cSCC. There are also a few rare congenital diseases predisposed to cutaneous malignancy. In certain geographic locations, exposure to arsenic in well water or from industrial sources may significantly increase the risk of cSCC. ==Additional images==

File:Biopsy proven Squamous Cell Carcinoma- 2014-05-27 05-13.jpg|Biopsy-proven cutaneous squamous-cell carcinoma File:Squamous-carcinoma-of-dorsum-of-hand.jpg|Squamous-cell carcinoma of the dorsum of the hand File:Bowen11.jpg|cSCC in situ (''Bowen's disease'') File:Squamous Cell Carcinoma, Right Upper Cheek.png|cSCC of the right upper cheek; lesion outlined in blue with a dashed line prior to biopsy File:Giant squamous cell carcinoma of the cheek.jpg|Giant squamous cell carcinoma of the cheek == See also ==