What is cutaneous squamous cell carcinoma?
Cutaneous squamous cell carcinoma (SCC) is a keratinocyte or non-melanoma skin cancer formed by the uncontrolled growth and replication of squamous cells in the epidermis. The keratin produced by these cells is a horny protein that normally forms skin, hair, and nails.
Cutaneous SCC is invasive into the dermis and may rarely metastasise (spread to other parts of the body). The more superficial forms of cutaneous SCC confined within the epidermis are known as intraepidermal SCC or SCC in situ.
Squamous cell carcinoma in skin of colour
What is skin of colour?
‘Skin of colour’ is a subjective term referring to a natural skin that is ‘darker’ than white (ie, yellow, brown, or black skin). When compared against a graded assessment of skin colour types, such as the Fitzpatrick phototypes, skin of colour may refer to skin classified as type IV or higher . In some contexts, skin of colour is also used to describe the skin type of different non-white ethnic groups, including those of African, Asian, South American, Pacific Island, Maori, Middle Eastern, and Hispanic descent . [See Ethnic dermatology]
Who gets cutaneous squamous cell carcinoma?
Cutaneous SCC is among the most commonly diagnosed cancers worldwide .
- Cutaneous SCC accounts for 15–25% of all diagnosed skin cancers and an estimated 75% of non-melanoma skin cancer-related deaths .
- The highest incidence of cutaneous SCC is seen in white-skinned individuals.
- Cutaneous SCC is the second most common form of skin cancer seen in Caucasians, Asians, and Hispanics after basal cell carcinoma.
- It is the most common form of skin cancer seen in blacks and Asian Indians.
The reported incidence rates for cutaneous SCC vary across different studies and periods; incidence rates per 100,000 population across the last 50 years have included:
- 0.16–2.9 in Chinese [4,5]
- 1.4 in Asian Indians 
- 3 in Blacks (estimated) 
- 6 in New Zealand Maori (including basal cell carcinoma) .
When compared to skin of colour, the cutaneous SCC incidence rates in white-skinned people show a significantly stronger correlation with geographic location . For instance, Australia and New Zealand, which share a similar latitude, have the highest reported incidence of cutaneous SCC in the world, with reports of 228–1332 and 124–598 cases per 100,000 for Australia and New Zealand, respectively, in the mid-1990s [3,8]. In comparison, incidence rates in Europe were 9–28.9 per 100,000 in the population [3,8].
The global incidence rates of cutaneous SCC are increasing, especially in white-skinned people [8,9]. Over the last few decades, it has been estimated the cutaneous SCC incidence rate has doubled or tripled across the United States, Australia and Europe . This trend is thought to be related to changes in popular recreational activities and clothing styles, resulting in increased cumulative sun exposure. The majority (~80%) of diagnoses occur in men and women over 60 years of age regardless of skin colour . Men are much more likely than women to develop cutaneous SCC — at double the incidence in some locations [8,9].
Risk factors for cutaneous SCC
Cutaneous SCC is more common in individuals with :
- Previous SCC, basal cell carcinoma, or melanoma
- Actinic keratoses
- Outdoor occupations or recreational activities
- A positive smoking status
- Fair skin, blue eyes, and blond or red hair
- Previous cutaneous injury or scarring from thermal burns or skin disease (eg, cutaneous lupus erythematosus, epidermolysis bullosa, leg ulcers)
- Chronic ulceration
- Ionising radiation, exposure to arsenic, and immune deficiency due to disease (eg, chronic lymphocytic leukaemia) or immunosuppressive drugs. Organ transplant recipients have a massively increased risk of developing SCC.
Exposure to ultraviolet (UV) B radiation is a significant risk factor for cutaneous SCC in Caucasians; in skin of colour, scarring may be more significant . There is a 20–40% risk of cutaneous SCC in chronically inflamed, ulcerated, or scarred skin leading to metastasis, compared with a 1–4% risk in sun-damaged skin .
What causes cutaneous squamous cell carcinoma?
Cutaneous SCC is triggered by an abnormal genetic transformation.
More about mutations to DNA
In white skin, oncogenetic transformation is related to sun exposure, with UVA and UVB radiation damaging and mutating the DNA of these cells . For instance, cutaneous SCC cells have frequently demonstrated mutations to the p53 tumour suppressor gene — a gene that normally functions to repair damaged DNA and prevent the development of tumours . Mutations to this gene may alter its function as p53 mutations are frequently found in many other types of malignancies [8,9]. Similarly, UV exposure can mutate signalling pathways that regulate cell activity, such as the epidermal growth factor receptor (EGFR), RAS, Fyn, or p16INK4a pathways. UV radiation may also suppress the ability of the immune system to detect to destroy tumour cells. More significant immunosuppression, such as in transplant patients, may allow infection by the human papillomavirus strains implicated in causing cutaneous SCC development .
In darker skin, a higher content of UV radiation-absorbing melanin is thought to protect the DNA from mutation and damage.
However, cutaneous SCCs may also arise in areas not exposed to sunlight or outside the skin. As the rates of these cutaneous SCCs can be higher in non-white-skinned ethic groups or display a hereditary pattern, it is thought genetic processes outside of skin pigmentation influence cutaneous SCC development . For instance, even in individuals with the same skin type, variants of the melanocortin one receptor (MC1R) gene are believed to increase the risk of cutaneous SCC .
What are the clinical features of cutaneous squamous cell carcinoma?
Cutaneous SCC can occur anywhere on the skin. In white-skinned people, this is typically in areas frequently exposed to the sun . It is estimated that 60–65% of cutaneous SCCs initially arise from actinic keratosis. Others may arise from intraepidermal carcinoma. In skin of colour, cutaneous SCC more frequently develops in non-sun-exposed areas, such as the legs and feet or in the anogenital region .
- Are typically described as firm, raised nodules or plaques with a crusted or scaly surface 
- Grow over weeks to months
- May be millimetres to several centimetres in diameter
- Can be tender
- May also present as chronic non-healing ulcers .
Cutaneous squamous cell carcinoma subtypes
Subtypes of cutaneous SCC include :
- Cutaneous horn, a conical projection from the skin formed of excessive keratin
- Keratoacanthoma, a rapidly growing nodule with a central scale that may shrink and resolve without treatment after a few weeks to months
- Carcinoma cuniculatum (verrucous carcinoma), a slow-growing, wart-like tumour on the sole
- Multiple eruptive SCC/keratoacanthoma-like lesions arising in syndromes (such as multiple self-healing squamous epitheliomas of Ferguson-Smith and Grzybowski syndrome).
Classification of cutaneous squamous cell carcinoma by risk
Cutaneous SCCs can be classified as low or high risk; high-risk features of cutaneous SCC regardless of skin colour include :
- Arising in older or immunosuppressed individuals
- Location on the ear, lip, central face, hands, feet, or genitalia
- Diameter ≥ 2 cm
- Histological thickness > 2 mm, poorly differentiated histology, or with the invasion of the subcutaneous tissue, nerves and blood vessels.
In skin of colour, cutaneous SCC arising from the perianal region or scarred skin is high risk due to relatively high metastasis rates .
More about risk
Clinicians or pathologists may also define risk by the subtype of SCC. Currently, there are no definitive ranking systems used to classify cutaneous SCCs, although the following system has been proposed :
- Low-risk SCC:
- SCC arising from actinic keratosis
- HPV-associated SCC
- Trichilemmal carcinoma
- Spindle cell SCC not associated with radiation
- Intermediate-risk SCC:
- Adenoid (acantholytic) SCC
- Intraepidermal epithelioma (Borst–Jadassohn) with invasion
- Lymphoepithelioma-like carcinoma
- High-risk SCC:
- Indeterminate-risk SCC:
- Clear-cell SCC
- Signet ring cell SCC
- Papillary SCC
- Pigmented SCC
- Follicular SCC
- SCC derived from adnexal cysts
- Squamous eccrine ductal carcinoma.
How is cutaneous squamous cell carcinoma diagnosed?
Cutaneous SCC is usually suspected during a physical examination, often with the aid of a dermatoscope. In skin of colour, special attention may need to be given to areas not typically exposed to the sun and scarred or inflamed skin .
Suspicious lesions are usually surgically removed for pathological examination and treatment (diagnostic excision).
Staging cutaneous SCCs
In patients with high-risk cutaneous SCC, it may be important to determine the depth of tumour invasion and the spread to surrounding tissue (disease staging). The seventh edition of the American Joint Committee on Cancer (AJCC) staging system for cutaneous SCC is commonly used .
The AJCC tumour staging for cutaneous SCC is as follows :
- TX: Primary tumour cannot be assessed
- T0: No evidence of primary tumour
- Tis: Carcinoma in situ
- T1: Tumour ≤ 2 cm in greatest dimension with < 2 high-risk features
- T2: Tumour > 2 cm in greatest dimension with or without one additional high-risk feature, or any size with ≥ two high-risk features
- T3: Tumour with the invasion of maxilla, mandible, orbit, or temporal bone
- T4: Tumour with the invasion of the skeleton (axial or appendicular) or perineural invasion of the skull base.
(High-risk features include depth [> 2-mm thickness; Clark level of dermal invasion ≥ IV]; perineural invasion; location [primary site ear; primary site non-glabrous lip]; and differentiation [poorly differentiated or undifferentiated].)
The AJCC nodal staging for cutaneous SCC is as follows :
- NX: Regional lymph nodes cannot be assessed
- N0: No regional lymph node metastasis
- N1: Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension
- N2: Metastasis in single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension
- N2a: Metastasis in single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension
- N2b: Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension
- N2c: Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension
- N3: Metastasis in lymph node, > 6 cm in greatest dimension.
(The sixth edition of the AJCC staging system classified regional lymph nodes into absence [N0] or presence [N1] of lymph node metastasis; the seventh edition incorporates other prognostic factors, including size, number, and location of regional lymph node metastases.)
To determine the stage of cutaneous SCC, the following investigations are usually considered in advanced cases:
- Ultrasound scans
- CT scans
- MRI scans
- Regional lymph node examinations
- Lymph node biopsy
- A biopsy of another tissue.
What is the differential diagnosis for cutaneous squamous cell carcinoma?
The main lesions that are confused with SCC are:
More about the differential diagnosis for cutaneous SCC
Other differential diagnoses for cutaneous SCC include:
Premalignant or malignant lesions:
- Actinic cheilitis (lip keratoses)
- Basosquamous carcinoma
- Amelanotic melanoma
- Oral intraepithelial carcinoma (mouth lesions)
- Cutaneous T-cell lymphoma
- Bowenoid papulosis
- Atypical fibroxanthoma
- Cutaneous metastasis
- Seborrhoeic keratosis
- Common wart or verruca
- Pyogenic granuloma
- Prurigo nodularis
- Thermal burn
- Allergic contact dermatitis
- Atopic dermatitis
- Lichen simplex chronicus
- Lichen planus
- Lupus erythematosus.
Cutaneous SCC may occur near or within skin affected by chronic conditions (eg, psoriasis and lichen planus). In these cases, especially where the chronic condition is widespread or poorly controlled, differentiating between lesions can be more difficult.
Compared to white skin, cutaneous SCCs in skin of colour show a more significant association with chronic inflammatory or scarring processes in the skin (Marjolin ulcer) .
What is the treatment for cutaneous squamous cell carcinoma?
Surgical excision is the recommended first-line treatment, regardless of skin colour . Recommendations for excision margins are as follows :
- Low risk, primary cutaneous SCC less than < 2 cm in diameter is removed with a 4-mm margin of surrounding tissue
- High risk, cutaneous SCC > 2 cm is removed with a 6-mm margin of surrounding tissue, especially if they are:
- Classified as moderately or poorly differentiated
- Extending into subcutaneous tissues
- Present on the ear, lip, scalp, eyelid, or nose
Other methods of removal include :
- Shave, curettage and cautery, and electrocautery for low-risk tumours on trunk and limbs
- Cryotherapy for very small, thin, low-risk tumours
- Mohs micrographic surgery for large facial lesions with indistinct margins or recurrent tumours
- Radiotherapy for inoperable tumours, patients unsuitable for surgery, or as an adjuvant to surgery.
- Currently, there is insufficient evidence to determine whether cryotherapy or fluorouracil is a superior treatment .
- Note that the use of imiquimod for intraepidermal SCC is off-licence in New Zealand.
What is the treatment for advanced or metastatic squamous cell carcinoma?
Locally advanced primary, recurrent, or metastatic SCCs require multidisciplinary consultation. A combination of treatments may be used for these aggressive tumours, including:
- Experimental targeted therapy using epidermal growth factor receptor (EGFR) inhibitors (these are not subsidised in New Zealand for use in cutaneous SCC).
The 2015 European consensus-based interdisciplinary guidelines for locally advanced or metastatic cutaneous SCCs make the recommendations below .
- Surgery should involve the complete removal of the primary cutaneous SCC, in addition to in-transit or satellite metastases.
- Radiotherapy should be administered, with or without chemotherapy, in cases where surgery is unsuccessful or unfeasible. Radiotherapy may also be used as palliative treatment to limit tumour growth into adjacent areas, provide pain relief, and stop any haemorrhaging.
- There is no established chemotherapy regimen for cutaneous SCC. Stage IV (metastatic) cutaneous SCC has shown remission in response to chemotherapy; however, the evidence is limited and the remission is often only observed for a short period of time.
- EGFR inhibitors may be considered following the failure of chemotherapy, but there is mixed evidence of their effectiveness.
Follow-up for cutaneous squamous cell carcinoma
There are no established guidelines for follow-up. Follow-up is generally recommended given that 30–50% of patients with an SCC are likely to develop another within five years . The time between follow-ups is typically based on the risk of new lesions, recurrences, or metastases. For patients with a lower risk, an annual follow-up may be sufficient. Patients with a higher risk (eg, renal transplant patients on immunosuppressant medication) may require more closely spaced follow-ups .
Cutaneous squamous cell carcinoma prevention in skin of colour
Compared to white-skinned individuals, the association between sun exposure and cutaneous SCC development is less prominent. Regardless, regular self-skin examination or skin checks by a clinician can help identify cutaneous SCCs earlier. It is also still potentially beneficial to minimise sun exposure, given that genetic processes outside skin pigmentation can influence the risk of cutaneous SCC development . Sun protection could involve:
- Staying indoors or under the shade in the middle of the day
- Wearing covering clothing
- Applying high protection factor SPF50+ broad-spectrum topical sunscreens generously to exposed skin if outdoors
- Avoiding indoor tanning (sun beds and solaria).
In individuals with multiple cutaneous SCCs or individuals at high risk of developing cutaneous SCCs, oral retinoids (ie, acitretin, isotretinoin) may slow tumour growth or the rate of new tumour development . However, these medications often exhibit side effects that, while not fatal, may prove a nuisance in everyday life (ie, dry skin and mucous membranes). They are also contraindicated in pregnancy due to a high risk of teratogenesis (birth deformities).
What is the outcome for cutaneous squamous cell carcinoma in skin of colour?
Successful treatment of cutaneous SCC is dependent on tumour size and invasion at the time of diagnosis. While most SCCs can be cured with treatment, people with skin of colour tend to present with more advanced cutaneous SCCs — especially if they occur on scarred or inflamed skin. As advanced cutaneous SCCs are associated with lower survival rates, treatment outcomes in skin of colour may be poorer .
More on prognosis
Cutaneous SCCs > 20 mm in diameter or 2 mm in depth are associated with higher rates of recurrence or mortality. It has been estimated that the 10-year survival rate in patients with cutaneous SCC that has spread to lymph nodes is approximately 20%, and < 10% if distant metastases have occurred .
It is currently unknown why people with skin of colour tend to present with more advanced cutaneous SCCs compared to white-skinned individuals. This difference may be due to :
- Delayed diagnosis
- Delayed presentation due to misperceptions related to skin cancer susceptibility
- A tendency for cutaneous SCC to be more aggressive in areas typically unexposed to the sun.