Squamous cell carcinoma (SCC) is the second most common form of skin cancer after basal cell carcinoma (BCC). In 1775, Percival Pott published “Chirurgical Observations Relative to the Cancer of the Scrotum” in which he detailed the primary development and metastatic progression of lesions involving the scrotum of chimney sweeps.¹ The publication was the first to identify a carcinogen and its occupational link to malignancy. The first detailed clinical description of BCC was by Arthur Jacob half a century later.¹ In 1828, Jean-Nicolas Marjolin described malignant transformation within traumatic scars, while it is reported that in 1860, Heurteux first described an instance of carcinoma in a burn scar, a condition that has eponymously come to be known as Marjolin’s ulcer.¹

Squamous cell carcinoma usually occurs on skin affected by chronic exposure to sunlight. It is less common than BCC, occurring approximately four times less frequently. The incidence of SCC has risen more sharply than that of BCC in recent decades and this change has been attributed to increased cumulative UV exposure.² Globally, the highest incidence of SCC is in Australia where the rate is 387 per 100,000 person-years, while the lowest recorded rates are in parts of Africa.^3,4 SCC rates have been shown to vary with latitude, with higher rates documented toward the equator.³ There is an overall gender disparity of approximately 2:1, with lesions affecting men more frequently than women.³ However, when a young population (below the age of 40) is analyzed, there is a similar incidence in men and women.⁵ SCC is rare below the age of 25, with less than 1% of all lesions occurring in this age group.⁶ The incidence of SCC rises dramatically from age 50 in Australia and the cumulative risk of developing an SCC by age 70 is reported to be 34% and 22% for men and women, respectively.^3,6

Anatomically, SCC most commonly occurs in the head and neck region, with frequent involvement of the nose, ears, and cheeks.⁷ It is also common for SCC to occur on the upper limbs, with frequent involvement of the hands and to a slightly lesser extent the forearm. The relative density of SCC in parts of the body such as the trunk and buttocks, which are typically protected from exposure to solar radiation, is lower. However, variations in sartorial, cultural, and occupational practices between the sexes are reflected in the anatomical distribution of lesions.⁷

Squamous cell carcinomas can metastasize and their propensity for metastatic spread is widely reported in the literature. The reported rate of metastasis ranges between 0.5% and 16%.⁸ Regional lymph nodes are the most common site for metastatic spread; however, distant disease involving bones, lung, and other visceral structures occur in 5% to 10% of patients with metastatic disease.

Exposure to UV radiation

Exposure to ultraviolet (UV) radiation is the most significant among a number of well-documented risk factors for the development of cutaneous SCC. The UV band of the electromagnetic spectrum extends from 10- to 400-nm wavelength with Ultraviolet A (UVA: long wave, 320- to 400-nm wavelength) and Ultraviolet B (UVB: medium wave, 280- to 320-nm wavelength) having the greatest clinical significance. Both UVA and UVB contribute to the development of SCC; however, UVB is more mutagenic, with UVB radiation around 300 nm is believed to cause most harm while radiation around 380 nm in the UVA range produces an effect that is orders of magnitude smaller.⁹ UVB radiation causes pathognomonic covalent bond formation between adjacent pyrimidines in the TP53 gene, leading to cytosine (C) to thymine (T) substitutions or cytosine dimer or thymine dimer mutations at dipyrimidine sites.¹⁰ UVB levels vary with latitude and there is a corresponding variation in the incidence of SCC.⁹ In an Australian study, approximately 3.5 times lower rates of SCC were noted in the south of the continent when compared to the north.³ SCC rates have also been shown to vary with UV exposure both in childhood and in adult life.⁹ Children who are born or move to areas with high ambient solar radiation prior to age 10 suffer a higher risk of SCC later in life, while people who reside in an area with low solar radiation and only migrate to a region with high ambient radiation after the age of 20 suffer a relative risk of 0.36, an almost two-thirds reduction when compared to individuals who were born in an area with high ambient solar radiation.⁹ In adults, occupational exposure to sunlight increases the relative risk of developing SCC by 1.64.⁹ Sunburn at any age shows no statistically significant increase in relative risk for SCC; however, the varying level of recreational sun exposure in this cohort is a confounding factor.

Skin Phototype

Skin phototype and the propensity to develop a tan in response to sun exposure play an important role in assessing SCC risk. Individuals with lighter skin phototypes exhibit a relative risk of developing SCC 2.3 times greater than those with darker skin.⁹ Likewise individuals who are able to produce a deep, moderate, light, or no tan exhibit relative risks of 1.0, 2.3, 4.6, and 6.9, respectively.⁹ The use of tanning devices has been shown to increase the risk developing SCC. Individuals who have had any exposure to a tanning device demonstrate an odds ratio of 2.5 for developing SCC when compared to the general population.¹¹ Furthermore the age of initial exposure to a tanning devices significantly modulates the risk, with individuals who were less than 20 years of age at first use demonstrating a substantially elevated odds ratio of 3.6 for SCC.¹¹ Psoralen and UVA (PUVA) is used medically to treat psoriasis and other dermatological conditions. Long-term prospective studies have demonstrated that exposure to 351 to 450 treatments of PUVA leads to a sixfold increase in SCC incidence, while greater than 450 treatments lead to a tenfold increase.¹²

Immunosuppression

Immunosuppression, either medically induced or due to disease, greatly increases the risk of SCC. Chronic immunosuppression in the context of organ transplantation has been shown to increase SCC incidence by as much as 82 times when compared to the general population,¹³ and there is also a reversal of the usual SCC:BCC ratio in certain transplant groups.¹⁴ The incidence of post-transplant SCC varies with latitude and Australian studies have shown that 45% of patients developed SCC within 10 years of organ transplantation, while studies from Holland, England, and Italy have reported a 10% to 15% incidence at 10 years.¹⁵ Furthermore, proximity to the equator has been shown to result in transplant patients developing cutaneous malignancies at a younger age.¹⁴ Cutaneous malignancies are the largest cause of death within 10 years in heart transplant patients, with SCC more likely to present with multiple lesions, recurrence, and metastatic disease than in the general population.¹⁴ In the context of nontransplant, medically-induced immunosuppression where lower dose glucocorticoids are administered to treat a myriad of disorders, a specifically increased risk of developing SCC has been established, with an adjusted odds ratio of 2.31 being demonstrated in a large trial.¹⁶

It is well established that nontransplant immunosuppressive disorders such as human immunodeficiency virus (HIV) infection and chronic lymphocytic leukemia (CLL) increase the risk of developing SCC. In a study of HIV patients, it was noted that lesions occurred at a younger age with a higher risk of recurrence, metastasis, and mortality when compared to the general population. Patients with Non-Hodgkin’s lymphoma, of which CLL is a subtype, have been shown to have a higher risk of developing SCC, with relative risks of 2.0 to 8.6 reported in the literature.¹⁷ There is also evidence that SCC behaves more aggressively in patients with CLL, with a demonstrated increase in the rates of local recurrence, metastatic disease, and mortality.^17,18

Human papillomavirus (HPV) infection is more prevalent in immunocompromised patients and HPV has been associated with the development of SCC. A high HPV prevalence (33% to 84%) has been noted in SCCs that develop in organ transplant recipients.¹⁹ The same cohort of patients also demonstrates a steady increase in the incidence of warts and other cutaneous changes associated with HPV post transplantation.¹⁹ HPV beta subtypes may be of particular relevance to immunosuppression-related SCC.²⁰

Previous SCC

A diagnosis of SCC significantly increases the likelihood of developing further primary lesions. A past diagnosis of SCC increases the relative risk of developing a new primary lesion by 2.79 times; however, a previous BCC does not greatly elevate this risk of subsequent SCC.²¹ The cumulative probability of developing a new primary lesion in 1, 3, and 5 years after diagnosis of the index case is 9%, 19%, and 31%, respectively.²¹

Smoking

Exposure to tobacco smoke is a risk factor for cutaneous SCC and it has been shown to produce a 52% increase in its incidence.²² This increase is not dependent on the duration or number of cigarettes smoked; however, cessation of smoking has been shown to produce a long-term reduction in incidence from 52% to 21%.²² Smoking cessation should therefore be encouraged in all patients with SCC who use tobacco.

Genetic Disorders

There are a number of genetic syndromes where there is a predisposition to develop SCC. These include epidermolysis bullosa, xeroderma pigmentosum, and epidermodysplasia verruciformis. Epidermolysis bullosa is comprised of a number of genodermatoses that demonstrate blistering and fragility of the skin. Mutations have been identified in ten different genes and this is reflected by the phenotypic heterogeneity of the condition.²³ Patients with junctional epidermolysis bullosa demonstrate an elevated risk of developing SCC; however, this is not to the same extent as patients with the generalized severe subtype of recessive dystrophic epidermolysis bullosa where there is a 90.1% cumulative risk of developing SCC by age 55.^24,25 Furthermore, the latter cohort of patients suffer a devastating 87.3% cumulative risk of death due to metastatic disease by age 45.²⁵ Malignant lesions in epidermolysis bullosa commonly occur in chronic wounds and appear to share some similarities with neoplasms arising from chronically inflamed burn scars, Marjolin’s ulcers, where SCCs with increased metastatic risk have a tendency to develop.

Xeroderma pigmentosum is an autosomal recessive disorder of the nucleotide excision DNA repair pathway, where patients demonstrate extreme sun sensitivity and a 10,000-fold increase in the risk of skin cancer.²³ Compared to the general population, where the median age for the development of nonmelanoma skin cancer is 67, patients with xeroderma pigmentosum develop the first lesion at a median age of 9 years and cutaneous malignancy is the most common cause of death.²³ Epidermodysplasia verruciformis is yet another rare autosomal recessive disorder where patients exhibit a large number of atypical warts, which are infected with ß human papillomavirus and commonly demonstrate malignant transformation into SCC.¹⁹

Arsenic

Arsenic, both in the environment and when used in medical therapies, has been associated with an increased risk of developing SCC. The primary environmental source of arsenic is from contaminated artesian ground water accessed via wells and chronic daily ingestion of arsenic at levels above 10 µg/kg is associated with dermatoses.^26,27 Arsenic exposure is associated with a higher incidence of SCC due to its activity as a cocarcinogen with UV radiation. Fowler’s solution that contains arsenic was previously used widely in the treatment of multiple ailments and this cohort of patients have also demonstrated an increased incidence of SCC.²⁸ Arsenic trioxide presently play a role in the treatment of hematological malignancies and its use in the treatment of promyelocytic leukemia likely confers an elevated risk of SCC as demonstrated by the other form of arsenic exposure.²⁹

Ionizing Radiation

Ionizing radiation has previously found wide utility in the management of inflammatory dermatoses and other medical conditions. An increase in the risk of developing SCC in the radiotherapy field has been identified with an odds ratio of 2.94.³⁰ The age at which exposure to ionizing radiation occurred also modulates the risk, with individuals who received treatment before the age of 20 years demonstrating greater risk.³⁰ The propensity for sunburn also plays an important role as these individuals are once again at increased risk of SCC this time due to the effects of ionizing radiation.³⁰

BRAF Inhibitors

Selective BRAF inhibitors are utilized in the treatment of metastatic melanoma and have been found to increase the risk of developing SCC. In an analysis of the cutaneous manifestations of treatment with dabrafenib, 20% of patients were noted to have developed one or more SCCs, which did not correspond to the typical anatomical distribution of lesions found in the general population.³¹ BRAF inhibitor-induced proliferative squamous lesions are thought to be caused by paradoxical activation of RAS in keratinocytes, particularly cells harboring UV-induced RAS mutations.³² The incidence is dramatically reduced when BRAF inhibitors are given in combination with MEK inhibitors.³³

UV-induced mutations in the TP53 tumor suppressor gene can be detected in approximately 90% of SCCs.³⁴ Mutations in TP53 result in uncontrolled proliferation of cells. Squamous epithelium with significant UV exposure demonstrates an overexpression of p53 and UV radiation causes pathognomonic cytosine (C) to thymine (T) substitutions or CC to TT mutations, which are demonstrated in the majority of SCCs.³⁵ Cutaneous SCCs also contain high levels of p53, while normal tissue contains a low level. Mutant p53 has been noted to accumulate within the cell cytoplasm, while wild-type p53 is rapidly degraded and cleared from cells.³⁴ UV-induced damage at the molecular level is the primary cause of SCC; however, RAS mutations are also involved in a smaller subset of cases.

The RAS pathway is involved in the development of SCCs, with 10% to 30% of lesions demonstrating activating point mutations.³⁶ RAS mutations are particularly prevalent in SCCs that develop in patients undergoing BRAF inhibitor treatment for melanoma. Hair follicle bulge cells demonstrate susceptibility to RAS overexpression and are considered a cell of origin for SCC.³⁶

Human papillomavirus (HPV) is believed to have a role in causing some cutaneous SCC; however, the exact extent of involvement has not been clearly defined. Patients with epidermodysplasia verruciformis demonstrate homozygous mutations in either TMC6 or TMC8, which are believed to cause an aberration in cellular zinc homeostasis within keratinocytes leading to an immune deficiency and increased HPV susceptibility.¹⁹

Precursor Lesions

A number of precursor lesions have been identified that have a variable tendency for transformation into SCC. The most prevalent of these precursor lesions are actinic keratoses and Bowen’s disease; however, arsenical keratosis and PUVA keratosis exist as less common entities.

Actinic keratosis (AK) is a form of intraepidermal neoplasia that occurs on sun-damaged skin. It is common in older, fair-skinned individuals with a prevalence of 75% noted in an Australian Caucasian population aged 80 to 86 years.³⁷ AK often presents as a small area of erythematous and hyperkeratotic change that remains asymptomatic. Transformation of AK into invasive SCC is reported to occur on average in approximately 8% of lesions.³⁸ It has also been noted that concomitant AK is present in 82% to 97% of SCCs.^39,40