Science of Skin

Squamous Cell Carcinoma (SCC)

Snapshot
Other common terms:
SCC, SCC skin cancer, non-melanoma skin cancer, NMSC
ICD-10 classification: C44
Prevalence: Second most common form of skin cancer.
Causes: Chronic exposure of skin to UV radiation. Immunosuppression and certain medical conditions are known to dramatically increase the risk of SCC skin cancer
Symptoms: Vary dramatically from patient to patient. May present as firm, flesh-coloured, red or brown scaly papule or plaque, however they may also present as a non-healing ulcer, smooth nodule, conical horn or wart like growth.
t;strong>Treatments/cures: Surgery is mainstay of treatment, particularly for invasive SCC.
Differential diagnosis: Basal Cell Carcinoma skin cancer, actinic keratosis

Squamous Cell Carcinoma (SCC) is a malignant skin tumour which develops from keratinocytes from above the basal layer in the epidermis. Invasive SCC indicates that the cancer cells have grown into the deeper layers of the skin (dermis), whereas the term in-situ SCC indicate that the cancer cells remain in the upper layers of the skin (epidermis). SCC and Basal Cell Carcinoma (BCC) are the non-melanoma skin cancers and are the most common malignancy in humans.

Incidence

Squamous cell carcinoma
Squamous cell carcinoma skin cancer

SCC is the second most common form of skin cancer in the general populace after Basal Cell Carcinoma (BCC).

An exception to this prevalence is recorded in the organ transplant population where SCC is thought to be most common, due to the life-long obligatory use of immune suppressive medications by these patients. It has been found that organ transplant patients are 65 to 100 times more likely to develop skin cancer than those who have not undergone transplantation of a donor organ.

There is a direct correlation between the incidence of skin cancer and the amount of natural pigmentation of a person's skin. As clinical studies have regularly shown, darker individuals are less likely to contract Actinic Keratoses or SCCs. It is shown that African Americans who have undergone organ transplants have a lower incidence of skin cancer than patients of Caucasian origin.

SCC is more common in men than women (2:1). There is an inverse relationship between dark skin colour and SCC incidence, largely because of the protective effect of melanin. Thus, in individuals with dark skin such as descendants from Arab and African populations, SCC is rarely seen. People with fair (Caucasian) skin, blue eyes, fair complexion, red hair and Celtic ancestry are most at risk of SCC.

Incidence of SCC varies around the world. It is most common in Australia where many fair skinned people have been subject to extensive sun exposure with a predicted 1,332 per 100,000 for males and 755 per 100,000 for females. In the US the estimated incidence is 107 cases per 100,000 people, but determining the exact incidence is difficult because US health registries do not record non-melanoma skin cancer and incidence varies with geographical location.

The incidence of SCC is increasing due to higher UV exposures (ozone depletion, solarium use, increased outdoor activities, and changed clothing styles) and greater longevity. This has been paralleled by a decrease in mortality thought to be due to improved public awareness and aggressive management of high risk lesions.

Most SCCs are treatable. The overall risk of metastasis is 0.5-5% in the general population but is as 9% in organ transplant patients. Risk of metastasis, however, is highly depend on other factors and needs to be put in the context of each patient.

Metastatic SCC is associated with higher morbidity and mortality. Studies show that when surgical lymphadenectomy (removal of lymph nodes) is combined with radiotherapy, 73% patients will still be alive after 5 years. Metastatic SCC to the lungs or liver is mostly incurable.

Symptoms

The symptoms of SCCs can vary dramatically from patient to patient. They are commonly found on sun exposed areas, such as the face, ears, neck, arms or hands, but can also form on areas which are rarely exposed to light.

They usually evolve from a precursor lesion; either an Actinic Keratosis (AK) or Bowen’s disease. The development of pain, increasing size or elevation or ulceration often indicates transformation to SCC from a precancerous lesion.

SCCs are most commonly firm, flesh-coloured, erythematous (red) or pigmented (brown) scaly papule or plaque, however they may also present as a non-healing ulcer, smooth nodule, conical horn or wart like growth. In the early stages, an SCC will be mobile but with progressive invasion it becomes fixed to underlying tissues and immobile. SCCs can occur in the mouth (common in smokers), genital region, within areas of chronic inflammation and scarring, and on the lower lip.

Metastatic SCCs have a variety of presentations. These include large scaly papules or nodules resembling the primary lesion or clusters of pink or red papules with a keratotic core. Sometimes the first sign of metastatic SCC may be an easily palpable enlarged lymph node.

Causes

The development of SCC from normal keratinocytes begins with mutations in cellular DNA which lead to loss of control of cell growth. Cells proliferate and become resistant to apoptosis (programmed cell death). Subsequently, the abnormal cells penetrate through the basement membrane and invade other tissues.

Cumulative lifetime sun-exposure is the most important contributing factor to the development of SCCs. UV radiation causes mutations in cellular DNA that when left un-repaired lead to uncontrolled cell growth, proliferation and tumour formation. Also, UV radiation causes immunosuppression which impairs the cells capacity to repair the damaged DNA.  This allows for the DNA mutations to persist and rejection of the tumour does not occur.

Eumelanin (natural black/brown pigment) in the skin provides an element of protection from UV radiation by filtering and diffusing light, acting as a redux polymer and reducing reactive oxygen species. Individuals with darker skin, that has the tendency to tan easily without burning, have more eumelanin in their skin, and hence have less risk of developing SCCs.
Actinic Keratoses (AKs) are premalignant lesions that have been demonstrated to be the initial step along a continuum with invasive Squamous Cell Carcinomas (SCC) at the opposite end.
Other factors implicated in the development of SCC include:

  • increasing age
  • ionizing radiation (radiotherapy)
  • environmental carcinogens (arsenic, aromatic hydrocarbons)
  • immunosuppression (organ transplant recipients)
  • chronic inflammatory conditions, particularly those associated with scarring (e.g. venous ulcers, discoid lupus)
  • Human Papilloma Virus (HPV)
  • genetic skin conditions (xeroderma pigmentosum, albinism)
  • chronic heat exposure
  • smoking and alcohol consumption - particularly for SCC of the mouth, tongue and throat

How UV radiation causes squamous cell carcinoma skin cancer

Electromagnetic spectrum of causing SCC
Electromagnetic spectrum of causing SCC

DNA is the main chromophore for UVB radiation. When photons of UVB light are absorbed by the DNA, damage is caused to the DNA helix, often resulting in C-T single mutations or CC-TT tandem mutations. These are commonly called ‘signature’ mutations and are indicative of photo damage due to UVB light. The photo damage caused by UVA light is less well understood, but it is likely it also plays a role in the transformation from normal to abnormal cells.

These ‘signature’ mutations are nearly always found in the p53 tumour suppressor gene (p53 is responsible for ensuring all DNA is repaired before allowing the cell to recommence cell division) which is found in the early developmental stages of SCC.

Multiple insults to the skin from recurrent exposure to UV radiation results in a pathway beginning with photo damaged skin, progresses to AK and eventually to invasive SCC. Along this pathway other factors such as HPV infection and immunosuppression contribute to the abnormalities accumulating within the cell.

Prevention

Avoiding UV sun exposure is the most effective way to decrease the risk of SCCs and studies have shown that strict sun protection throughout life will prevent their development. The critical time is in childhood, hence education of young people about sun protection is particularly important.

Complete avoidance of the sun is obviously not practical, but the next best thing is to avoid the strong midday sun between 10am and 4pm. Also consistent application and reapplication of a broad-spectrum sunscreen, wearing UV protective clothing hats and sunglasses should always be employed.

Precursor lesions such as AK and SCC in-situ should be treated as these lesions of the skin are expected to decrease the incidence of SCCs.

Other preventative measures include the practice of safe sex, by using condoms to decrease transmission of HPV, the cessation of smoking and limiting alcohol consumption reduces one’s chance of oral SCCs.

Oral retinoids have been shown to prevent further developing mutation in keratinocytes and so may be used for maintenance of the skin. This is often used in high risk patients such as renal transplant recipients.

{pullquote}There are several steps that can be taken to reduce the risk of SCC developing:

  • Sun avoidance between 10am-4pm
  • Consistent application and reapplication of broad spectrum sunscreens
  • Wearing UV protective clothing hats and sunglasses
  • Treatment of precursor lesions
  • Cessation of smoking (for SCC of the mouth and neck mucosa)
  • Reduction of alcohol intake (for SCC of the mouth and neck mucosa{/pullquote}

Diagnosis

A skin biopsy is the method used to confirm a diagnosis of SCC. This can easily be done with either a shave excision with a scalpel or for more elevated lesions, a punch biopsy. The SCC will be given a grade depending on the degree of cellular abnormality noted on histologic examination. The depth or penetration, tumour thickness, hair follicle, muscle, nerve or bone involvement are also recorded so the lesion can be classified as low or high risk.

Treatment

Surgical excision is the treatment of choice for small primary SCCs. They should always be excised with a surgical margin of surrounding normal unaffected tissue, 2-3 mm for low risk lesions (depth less than 2mm).

Mohs microscopically controlled surgery is recommended for lesions with a depth greater than 6mm or diameter above 1cm. This type of surgery is also recommended in specific circumstances when the highest cure rate and minimal tissue destruction is required, such as tumours of the lip, eyelid, ears, genitals or nasal tip.

Radiation therapy can be used to treat superficially invasive to moderate-risk lesions. It is also used in conjunction with excisional surgery to treat residual microscopic disease and provide protection against recurrence and metastatic disease.

Destructive techniques such as electrocautery and curettage, cryotherapy, topical chemotherapy or photodynamic therapy are generally inappropriate for the treatment of invasive SCC because they are superficial and there is no control over histological margin.

Recurrence and metastasis (distant spread)

0.5-5% of SCCs metastasize, meaning that they spread to surrounding tissues. Metastasis occurs usually to local lymph nodes and mostly occurs 1-3 years after the primary lesion. In many cases metastasis is preceded by local recurrence. Metastasis tends to occur in tumours that are large in size, recurrent and involving nerves or other deep structures.

Follow up

Anyone who has had a diagnosis of SCC should be considered high risk for developing further SCCs and BCCs in his lifetime. Follow up with examination of sites of previous lesions should be assessed for recurrence and a full body skin check should be performed anywhere from 3 monthly to annually depending on the degree of risk of prior lesions. Lymph nodes should also be checked for spread of disease.

References

  • Anwar, J, Wrone, D A, Kimyai-Asadi, A & Alam, M. (2004) 'The Development of Actinic Keratosis into Invasive Squamous Cell Carcinoma: Evidence and Evolving Classication Schemes', Clinics in Dermatology. Vol 22, pp189-196.
  • Bernstein, S C, Lim, K K, brodland, D G & Heidelberg, K A (1996). 'The many faces of Squamous Cell Carcinoma', Dermatological Surgery. Vol 22(3), pp243-254.
  • Euvrard, S, Kanitakis, J, Decullier, et al. (2006) 'Subsequent Skin Cancers in Kidney and Heart Transplant Recipients after the First Squamous Cell Carcinoma' Transplantation. Vol 81(8), pp1093-1100.
  • Markey, A C, (1995). 'Etiology and Pathogenesis of Squamous Cell Carcinoma', Clinical Dermatology. Vol 13(6) pp537-543.
  • Oppel, T & Korting, H C. (2004) 'Actinic Keratosis: The Key Event in the Evolution from Photoaged Skin to Squamous Cell Carcinoma', Skin Pharmacology and Physiology. Vol 17(2), pp67-76.
  • Tsai T, Vu C, Henson D E (2005) "Cutaneous, ocular and visceral melanoma in African Americans and Caucasians", Melanoma Research. Vol 15, pp213-217.

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