Squamous cell carcinoma of skin

What is squamous cell carcinoma?

Primary cutaneous squamous cell carcinoma (SCC) is a malignant tumour that arises from the keratinising cells of the epidermis or its appendages. It is locally invasive and has the potential to metastasise to other organs of the body.¹

Who gets squamous cell carcinoma? (Epidemiology)

• Skin cancers are the most common cancers diagnosed and incidence is rising across the world despite knowledge and education about prevention.

• SCC is the second most common skin cancer (behind basal cell carcinoma (BCC)).¹ The incidence is rising worldwide.²

• Incidence varies by country, skin colour, and outdoor behaviour, and is as high as 400 per 100,000 population in Australia. The incidence is higher in Caucasians.³

• About 20% of non-melanoma skin cancers (NMSCs) are caused by SCC and 80% by BCC.

• There is a rising incidence with age. Men are more commonly affected, probably because of greater head and neck exposure to ultraviolet radiation (UVR).^{2 4}

Risk factors for squamous cell carcinoma

Chronic UVR exposure is the most important risk factor. This helps to explain the very high rates of skin cancer in countries like Australia, where fair-skinned, susceptible people are put at risk by sun exposure. The rise in UVR exposure produces more cases of squamous cell carcinoma in populations in equatorial zones.

• UV light (therefore there is increased risk with holidays in the sun, outdoor occupations and leisure pursuits, and using tanning beds).

• Susceptibility to UV light exposure: fair skin (skin that tans poorly), blonde or red hair.

• Chemical carcinogens: arsenic and chromium, soot (scrotal cancers in chimney sweeps), tar and pitch oils.⁵

• Human papillomavirus infection.

• Ionising radiation exposure.

• Immunodeficiency.

• Chronic inflammation: near chronic ulcers, around chronic sinuses (eg, osteomyelitis), lupus vulgaris (chronic form of cutaneous tuberculosis).

• Genetic conditions - eg, xeroderma pigmentosum and albinism.

• Pre-malignant conditions - eg, Bowen's disease, areas of skin showing actinic damage. Multiple actinic keratoses are associated with an estimated 10% lifetime risk of skin cancer. Keratoacanthomas may rarely progress to SCC.

Squamous cell carcinoma symptoms

Squamous cell carcinoma usually presents as an indurated nodular keratinising or crusted tumour that may ulcerate, or it may present as an ulcer without evidence of keratinisation.¹

• Typically, SCC presents as a non-healing ulcer or growth in one of the higher-risk sun-exposed areas. Most SCCs appear on the skin of the head and neck.

• The clinical appearance is very variable:
  

  • A small nodule enlarges and the centre becomes necrotic and sloughs, developing into an ulcer. The tumour therefore usually presents as an ulcerated lesion with hard, raised edges.

  • Slow-growing ulcer or reddish skin plaque.

  • Bleeding may occur from the tumour.

• SCC may give rise to local metastases or spread to local lymph nodes.⁶

Squamous cell carcinoma - forearm

By Dermanonymous (Own work), via Wikimedia Commons

Squamous cell carcinoma - cheek

By Dermanonymous (Own work), via Wikimedia Commons

Squamous cell carcinoma - nose

By unknown photographer, Public domain, via Wikimedia Commons

Differential diagnosis

There are a number of important conditions which can produce similar-looking skin lesions:

• Keratoacanthoma (can be difficult to differentiate even histologically).

• BCC.

• Malignant melanoma (particularly amelanotic malignant melanomas).

• Solar (actinic) keratosis.

• Pyogenic granuloma.

• Seborrhoeic warts (especially if traumatised or infected).

• Plantar warts or verrucas (beware periungual SCC).

Investigations

Investigation is primarily by visual inspection and removal for histology where necessary.⁸

However, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy have increased the diagnostic accuracy in terms of early recognition, better differential diagnosis, more precise selection of areas to biopsy and non-invasive monitoring of treatments.⁹

Skin biopsy

• Excisional biopsy (whole lesion excised):
  

  • Small lesions which are accessible and not in cosmetically sensitive areas or near to vital structures can be removed completely (see the separate article Minor Surgery in Primary Care).

  • For most lesions this can be performed under local anaesthesia.

  • The full thickness of skin should be taken to determine depth of spread.

  • The excision should be well wide of the margins to achieve clearance.

  • Shave biopsies should not be performed.

• Incisional or punch biopsy (part of lesion excised) is appropriate:
  

  • If the lesion is large.

  • In cosmetically sensitive areas.

  • When close to vital structures.

Further surgery is performed according to histology.

Further investigations

In advanced stages of disease, further investigations to assess the extent of disease may be required:

• Imaging including CT scanning (bone or soft tissue spread, particularly cervical lymph nodes) and MRI scanning (particularly for head and neck spread, perineural invasion).

• Clinically enlarged nodes should be examined histologically - eg, by fine-needle aspiration or excisional biopsy.¹

Referral

• Consider a suspected cancer pathway referral (for an appointment within two weeks) for people with a skin lesion that raises the suspicion of squamous cell carcinoma.⁷

• The Scottish Intercollegiate Guidelines Network (SIGN) guideline recommends prompt early referral if there have been high levels of cumulative psoralen plus ultraviolet A photochemotherapy, rapid tumour growth, poorly defined clinical margins or pain/dysaesthesia.¹⁰

Staging

For most patients with NMSC, no formal staging beyond clinical examination for lymphadenopathy is required.⁸

Tumour, node and metastasis (TNM) staging system for squamous cell carcinoma

Squamous cell carcinoma treatment and management^{8 11}

• There should be two levels of multidisciplinary teams: local hospital skin cancer multidisciplinary teams (LSMDTs) and specialist skin cancer multidisciplinary teams (SSMDTs).

• People with pre-cancerous skin lesions should either be treated entirely by their GP or referred for diagnosis, treatment and follow-up to doctors working in the community, who are members of the LSMDT/SSMDT.

• If there is any doubt about the diagnosis, people with pre-cancerous lesions should be referred directly to their local hospital skin cancer specialist. Where appropriate, follow-up of these patients may be undertaken by their own GP.

• All patients with an SCC or where the diagnosis is uncertain should be referred urgently to a doctor trained in the specialist diagnosis of skin malignancy, normally a dermatologist, who is a member of either an LSMDT or an SSMDT.

• In England, the target for patients with SCC referred through the two-week urgent GP referral route is that they must start their first definitive treatment within 62 days of GP referral. For all other patients with SCC in England, the target is that they must start their first definitive treatment within 31 days of the decision to treat.

• Patients with a high risk of recurrence of skin cancer or of new primary cancers should normally be followed up in hospital but should still be instructed in self-examination and provided with written and photographic information.

Management options⁸

The standard effective treatment is complete surgical excision and all excised specimens should be sent for histopathological examination. However, there is little evidence comparing the efficacy of different interventions for primary cutaneous squamous cell carcinomas.^{12 13} Where the other non-surgical treatments exclude histological confirmation of the diagnosis, an incisional biopsy for confirmation of the diagnosis should usually be obtained before treatment. Other surgical and non-surgical procedures include:

• Curettage and cautery/electrodesiccation:
  

  • Performed using a curette to remove soft material from the tumour. The base of the tumour is then destroyed, using either hyfrecation or cautery.

  • This may be used to treat small (less than 1 cm) in situ SCCs and pre-cancerous lesions.

  • It is safe and well tolerated, and usually produces a good cosmetic outcome.

  • It is suitable for patients with multiple lesions.

  • The histology may be difficult to interpret, as the lesion may be incompletely removed and margins of excision cannot be assessed optimally.

• Cryotherapy/cryosurgery:
  

  • Is a cost-effective treatment and is well established for small in-situ SCCs and pre-cancerous lesions.

  • Histology is not available unless an incisional biopsy is taken first.

• Topical treatment:
  

  • Imiquimod 5% cream is effective in treating actinic keratosis.

  • Fluorouracil (Efudix® 5% cream) is licensed for 'superficial malignant and pre-cancerous skin lesions'.

  • Diclofenac 3% gel is licensed for the treatment of actinic keratoses.

• Photodynamic therapy (PDT):
  

  • Involves the use of light therapy in combination with a topical photosensitising agent to destroy cancer cells.

  • Is used in the treatment of in-situ SCCs and actinic keratosis.

  • Evidence of efficacy for treating invasive SCCs is limited, recurrence rates are high, there is a risk of metastasis and re-treatment may be necessary.¹⁴

• Electrochemotherapy:¹⁵

  • Chemotherapy drugs are given first, either intravenously or directly into the tumour.

  • Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour, using either surface plates or needle electrodes.

  • There are no major concerns regarding the safety of electrochemotherapy for primary SCC but evidence on its efficacy is limited.

• Mohs' micrographic surgery:
  

  • Is a precise technique in which excision of the skin lesion is carried out in stages and each stage checked histologically.

  • It is advocated for use in cases where it is critical to obtain a clear margin while preserving the maximum amount of normal surrounding tissue.

  • This procedure is more often used in the treatment of BCCs.

• Radiotherapy:

  • Is a useful treatment for patients who cannot be, or prefer not to be, treated by surgery.

  • The cure rates are over 90% for most skin lesions, but the long-term cosmetic outcome, particularly for young patients, is inferior to that following other treatments.

  • The same area cannot be treated twice and so, if there is a recurrence, surgery is required, which may be more difficult than if the lesion had been removed surgically to start with.

  • Radiotherapy can also be used in cases when the margins of excision appear to be incomplete on histopathological examination.

  • Radiotherapy is curative for some cases of advanced inoperable disease.

  • Radiotherapy also has a role in the palliative treatment of patients with large, inoperable and recurrent SCC, or if there are inoperable metastases in lymph nodes or elsewhere.

  • Radiotherapy has a role in adjuvant treatment of extracapsular nodal disease following neck dissection.

Factors affecting metastatic potential of cutaneous squamous cell carcinoma¹

• Site: tumour location in order of increasing metastatic potential:
  

  • SCC arising at sun-exposed sites excluding the lip and ear.

  • SCC of the lip.

  • SCC of the ear.

  • Tumours arising in non-sun-exposed sites (eg, the perineum, sacrum, sole of foot).

  • SCC arising in areas of radiation or thermal injury, chronic draining sinuses, chronic ulcers, chronic inflammation or Bowen's disease.

• Diameter: tumours greater than 2 cm in diameter are twice as likely to recur locally and three times as likely to metastasise.

• Depth: tumours greater than 4 mm in depth (excluding surface layers of keratin) or extending down to the subcutaneous tissue (Clark level V) are more likely to recur and metastasise compared with thinner tumours.

• Histological differentiation: poorly differentiated tumours have a poorer prognosis, with more than double the local recurrence rate and triple the metastatic rate of better-differentiated SCC.

• Tumours with perineural involvement are more likely to recur and to metastasise.

• Host immunosuppression: tumours arising in patients who are immunosuppressed have a poorer prognosis.

• Previous treatment and treatment modality: the risk of local recurrence depends upon the treatment modality:
  

  • Locally recurrent disease itself is a risk factor for metastatic disease.

  • Local recurrence rates are considerably less with Mohs' micrographic surgery than with any other treatment modality.

Squamous cell carcinoma prognosis

• The overall mortality rate of cutaneous squamous cell carcinoma metastasis is low (<5%), but where distant metastases are present, the five-year survival rate is poor at around 25-40%.¹⁰

• Up to 95% of metastases and local recurrences are detected within five years of initial treatment, with 70-90% occurring within the first two years.¹⁷

Prevention of squamous cell carcinoma

• Avoiding sun exposure is the key to prevention, including:

  • Staying indoors or in the shade as much as possible between 11 am and 3 pm.

  • Covering up with clothes and a wide-brimmed hat when out in the sunshine.

  • Applying sunscreen of at least sun protection factor (SPF) 15 (SPF 30 for children or people with pale skin) which also has high ultraviolet A (UVA) protection

• Secondary prevention by early detection and effective management is also very important.