Squamous-cell carcinoma of the skin, squamous-cell skin cancer, epidermoid carcinoma, squamous-cell epithelioma of the skin
Cutaneous squamous-cell carcinoma tends to arise from
actinic keratoses (premalignant lesions); surface is usually scaly and often ulcerates (as shown here).
Cutaneous squamous-cell carcinoma (cSCC), also known as squamous-cell carcinoma of the skin or squamous-cell skin cancer, is one of the three principal types of
skin cancer, alongside
basal-cell carcinoma and
melanoma.[10] cSCC typically presents as a hard lump with a scaly surface, though it may also present as an
ulcer.[1] Onset and development often occurs over several months.[4] Compared to basal cell carcinoma, cSCC is more likely to
spread to distant areas.[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.[12][13]
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.[20]
Preventive measures against cSCC include minimizing exposure to ultraviolet radiation and the use of
sunscreen.[5][6] Surgical removal is the typical treatment method,[2] employing simple excision for minor cases or
Mohs surgery for more extensive instances.[2] Other options include
cryotherapy and
radiation therapy.[7] For cases with distant metastasis,
chemotherapy or
biologic therapy may be employed.[7]
As of 2015, approximately 2.2 million individuals globally were living with cSCC at any given time,[8] constituting about 20% of all skin cancer cases.[21] In the United States, approximately 12% of males and 7% of females are diagnosed with cSCC at some point in their lives.[2] While prognosis remains favorable in the absence of metastasis, upon distant spread the
five-year survival rate is markedly reduced to ~34%.[4][5] In 2015, global deaths attributed to cSCC numbered around 52,000.[9] The average age at diagnosis is approximately 66 years.[4] Following successful treatment of an initial cSCC lesion, there is a substantial risk of developing subsequent lesions.[2]
As of 2015, about 2.2 million people worldwide have cSCC at any given time. About 20% of all skin cancer cases consist of cSCC. About 12% of males and 7% of females in the United States develop cSCC at some point in time. While prognosis is usually good, when distant spread occurs
five-year survival is ~34%. In 2015, cSCC resulted in approximately 52,000 deaths globally. The mean age at diagnosis is around 66 years. Following the successful treatment of one case of cSCC, a person is at significant risk of developing further cSCC
lesions.
Signs and symptoms
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.[22]
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.[23][24][25]
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.[26] There is a risk of
metastasis starting more than 10 years[citation needed] after diagnosable appearance of squamous-cell carcinoma, but the risk is low,[specify] though much[specify] higher than with basal-cell carcinoma. Squamous-cell cancers of the lip and ears have high rates of local recurrence and distant metastasis.[27] 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.[28]
cSCC represents about 20% of the non-melanoma skin cancers; 80-90% of cSCCs with metastatic potential are located on the head and neck.[29]
Tobacco smoking also increases the risk for cutaneous squamous-cell carcinoma.[14][30]
The vast majority of cSCC cases are located on exposed 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 primary sign 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 than does basal-cell carcinoma, and may spread to the regional
lymph nodes,[31]
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.[40]
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.[41] 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.[42] The incidence of cSCC development increases with time posttransplant.[43] Heart and lung transplant recipients are at the highest risk of developing cSCC due to more intensive immunosuppressive medications used.[44]
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.[45] 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.[46]
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.[citation needed]
Histological 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.[citation needed]
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.[12]
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.[12]
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.[12] Depending on source, it is classified as precancerous[13] or cSCC in situ (technically cancerous but non-invasive).[47][48] In cSCC in situ (Bowen's disease), atypical
squamous cells proliferate through the whole thickness of the epidermis.[12] The entire tumor is confined to the epidermis and does not invade into the dermis.[12] 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.[12]
cSCC in situ, high magnification, demonstrating an intact basement membrane.[12]
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,[32][33]: 733 [34]: 656 [35] and the
vulva in females.[36] It mainly occurs in uncircumcised males,[36][49] over the age of 40.[39]
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.[12]
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.[12]
High magnification demonstrates the pleomorphism of the invading keratinocytes[12]
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.[12]
Moderately differentiated lesions of invasive cSCC show much less organization and maturation with significantly less keratin formation.[12]
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.[12]
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.[50] A 2016 review of sunscreen for preventing cutaneous squamous-cell carcinoma found insufficient evidence to demonstrate whether it was effective.[51]
Management
Most cutaneous squamous-cell carcinomas are removed with surgery. A few selected cases are treated with
topical medication. Surgical excision with a
free margin of healthy tissue is a frequent treatment modality. Radiotherapy, given as
external beam radiotherapy or as
brachytherapy (internal radiotherapy), can also be used to treat cSCC. There is little evidence comparing the effectiveness of different treatments for non-metastatic cSCC.[52]
Mohs surgery is frequently utilized; considered the treatment of choice for squamous-cell carcinoma of the skin, physicians have also utilized the method for the treatment of squamous-cell carcinoma of the mouth, throat, and neck.[53] An equivalent method of the
CCPDMA standards can be utilized by a pathologist in the absence of a Mohs-trained physician.
Radiation therapy is often used afterward in high risk cancer or patient types.[54] Radiation or
radiotherapy can also be a standalone option in treating cSCC. 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. An example of this kind of therapy is the high-dose brachytherapy Rhenium-SCT which makes use of the beta rays emitting property of
rhenium-188. The radiation source is enclosed in a compound which is applied to a thin protection foile directly over the lesion. This way the radiation source can be applied to complex locations and minimize radiation to healthy tissue.[55]
After removal of the cancer, closure of the skin for patients with a decreased amount of skin laxity involves a split-thickness skin graft. A donor site is chosen and enough skin is removed so that the donor site can heal on its own. Only the epidermis and a partial amount of dermis is taken from the donor site which allows the donor site to heal. Skin can be harvested using either a mechanical dermatome or Humby knife.[56]
Electrodessication and curettage (EDC) can be done on selected squamous-cell carcinoma of the skin. 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.[57]
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.[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.
Nodal spread:
Surgical block dissection if palpable nodes or in cases of Marjolin's ulcers but the benefit of prophylactic block lymph node dissection with Marjolin's ulcers is not proven.
Radiotherapy
Adjuvant therapy may be considered in those with high-risk cSCC even in the absence of evidence for local metastasis.
Imiquimod (Aldara) has been used with success for squamous-cell carcinoma in situ of the skin and the penis, but the morbidity and discomfort of the treatment is severe. An advantage is the cosmetic result: after treatment, the skin resembles normal skin without the usual scarring and morbidity associated with standard excision. Imiquimod is not FDA-approved for any squamous-cell carcinoma.
In general, squamous-cell carcinomas have a high risk of local recurrence, and up to 50% do recur.[58] Frequent skin exams with a dermatologist is recommended after treatment.
Prognosis
The long-term outcome of squamous-cell carcinoma is dependent upon several factors: the sub-type 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%.[25][59][60]
When it does metastasize, the most commonly involved organs are the lungs, brain, bone and other skin locations.[61] 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.[62]
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%,[63] 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.
Epidemiology
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.[25]
A recent study estimated that there are between 180,000 and 400,000 cases of cSCC in the United States in 2013.[65] Risk factors for cSCC varies with age, gender, race, geography, and genetics. The incidence of cSCC increases with age and with those 75 years or older eing at a 5-10 times increased risk of developing cSCC as compared with those who are younger than 55 years old.[25] Males are affected with cSCC at a ratio of 3:1 in comparison to females.[25] Those who have light skin, red or blonde hair and light colored eyes are also at increased risk.[25]
Squamous-cell carcinoma of the skin can be found on all areas of the body but is most common on frequently sun-exposed areas, such as the face, legs and arms.[66] 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[67] or from industrial sources may significantly increase the risk of cSCC.[26]
Additional images
Biopsy-proven cutaneous squamous-cell carcinoma
Squamous-cell carcinoma of the dorsum of the hand
cSCC in situ (Bowen's disease)
cSCC of the right upper cheek; lesion outlined in blue with a dashed line prior to biopsy
^
abcdefghijGandhi SA, Kampp J (November 2015). "Skin Cancer Epidemiology, Detection, and Management". The Medical Clinics of North America. 99 (6): 1323–1335.
doi:
10.1016/j.mcna.2015.06.002.
PMID26476255.
^
ab"Skin Cancer Treatment". National Cancer Institute. 21 June 2017.
Archived from the original on 4 July 2017. Retrieved 2 July 2017.
^Cakir BÖ, Adamson P, Cingi C (November 2012). "Epidemiology and economic burden of nonmelanoma skin cancer". Facial Plastic Surgery Clinics of North America. 20 (4): 419–422.
doi:
10.1016/j.fsc.2012.07.004.
PMID23084294.
^Bardhan A, Bruckner-Tuderman L, Chapple IL, Fine JD, Harper N, Has C, et al. (September 2020). "Epidermolysis bullosa". Nature Reviews. Disease Primers. 6 (1): 78.
doi:
10.1038/s41572-020-0210-0.
PMID32973163.
S2CID221861310.
^
abMarks Jr JG (2006). Lookingbill and Marks' principles of dermatology (4th ed.). Philadelphia, PA: Saunders Elsevier. p. 63.
ISBN978-1-4160-3185-7.
^
abFreedberg IM, Fitzpatrick TB (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). New York: McGraw-Hill, Medical Pub. Division.
ISBN978-0-07-138076-8.
^
abJames WD, Berger TG, Elston DM (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier.
ISBN0-7216-2921-0.
^
abRapini RP, Bolognia JL, Jorizzo JL (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1050.
ISBN978-1-4160-2999-1.
^Tessari G, Girolomoni G (October 2012). "Nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and management". Dermatologic Surgery. 38 (10): 1622–1630.
doi:
10.1111/j.1524-4725.2012.02520.x.
PMID22805312.
S2CID40490951.
^O'Reilly Zwald F, Brown M (August 2011). "Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients". Journal of the American Academy of Dermatology. 65 (2): 253–261.
doi:
10.1016/j.jaad.2010.11.062.
PMID21763561.
^[1], Hallock G. Squamous Cell Carcinoma Excision from Right Forearm with Split-Thickness Skin Graft from the Thigh. J Med Ins. 2020;2020(290.16) doi:
https://jomi.com/article/290.16
^Gross MD, Cardash HS (March 1989). "Transferring anterior occlusal guidance to the articulator". The Journal of Prosthetic Dentistry. 61 (3): 282–285.
doi:
10.1016/0022-3913(89)90128-5.
PMID2921745.
^Chollet A, Hohl D, Perrier P (April 2012). "[Risk of cutaneous squamous cell carcinomas: the role of clinical and pathological reports]". Revue Médicale Suisse. 8 (335): 743–746.
PMID22545495.
^Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, Breuninger H (August 2008). "Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study". The Lancet. Oncology. 9 (8): 713–720.
doi:
10.1016/S1470-2045(08)70178-5.
PMID18617440.
^Bethune G, Campbell J, Rocker A, Bell D, Rendon R, Merrimen J (May 2012). "Clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a North American population". Urology. 79 (5): 1092–1097.
doi:
10.1016/j.urology.2011.12.048.
PMID22386252.
^Karia PS, Han J, Schmults CD (June 2013). "Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012". Journal of the American Academy of Dermatology. 68 (6): 957–966.
doi:
10.1016/j.jaad.2012.11.037.
PMID23375456.