Approach

The methods used to treat squamous cell carcinoma (SCC) vary depending on tumour type, size and location, patient history, patient comorbidities and immune status, and practitioner. Treatment can be surgical, locally destructive (cryotherapy, electrodesiccation, photodynamic therapy), or pharmacological.[74][90]​ Systemic treatment, using chemotherapy (oral, intravenous, and intra-arterial), leads to objective responses in locally advanced cutaneous SCCs that are not amenable to local cure.[91]

Sunscreens with UV-A and UV-B spectrum coverage or sunblocks should be advised for secondary prevention. Similarly, physical sun protection with clothing and hats, and sun avoidance should be emphasised.[42][67]

Pre-treatment management

In cases of diagnostic uncertainty, histopathology should be obtained by taking a biopsy that is a representative sample of the presenting lesion before any treatment is planned.[90]

UK guidelines recommend that, prior to performing a diagnostic biopsy or a management procure (e.g., cryotherapy), the following steps are implemented:[90]

  • Record the maximum lesion dimension (diameter in mm) and immune status of the patient.

  • Take a good quality photograph of the lesion for the patient record.

  • In multisite disease, the lesions treated should be marked on the photographs to prevent wrong site surgery.

All treatment options should be discussed with patients and their carers before a management decision is reached.[90]

SCC in situ (Bowen's disease)

SCC that is limited to the epidermis may be treated with non-surgical options such as topical chemotherapy, destructive treatment, and photodynamic therapy.[74]

Evidence from systematic reviews comparing types of non-excisional treatment for SCCs varies. One review concluded that no one type of treatment is superior to another, a second subsequent review was unable to come to firm conclusions due to low-quality evidence, and a third systematic review reported that electrodessication and cryotherapy, in combination with curettage, are more effective than photodynamic therapy, fluorouracil, or imiquimod in treating SCC.[92][93][94]

Patients should be followed closely, and tumours that recur or do not respond should be excised.

All solid organ transplant recipients who present with actinic keratosis should be managed proactively, including field therapy with fluorouracil for those with numerous lesions, and low threshold for biopsy, to exclude invasive SCC.[89]

Topical chemotherapy

Topical chemotherapy with fluorouracil-based regimens (e.g., fluorouracil with or without calcipotriol) are preferred.[74] Fluorouracil targets abnormal cells by providing high local concentrations of this chemotherapeutic agent without adverse systemic effects, and has been demonstrated to have a significant clearance rate for SCC.[95][96]​​​​ The advantage of this approach is that numerous lesions in an affected area are treated. In addition, treatment can be performed at home. Responsive lesions will become erosive within a few days to weeks depending on the concentration of drug and frequency of application. After a crusted stage, the erosions re-epithelialise to leave cytologically normal skin.

Destructive therapy

Destructive therapy may include ablative laser vermilionectomy, ablative skin resurfacing, chemical peels, cryotherapy, curettage and electrodesiccation.[74] 

Local destruction with liquid nitrogen (cryotherapy) is commonly applied.[97][98]​ This often results in a delayed formation of a vesicle or bulla. In patients with darker skins, cryotherapy may cause hypopigmentation in the long term.

Electrodessication and curettage is another common method but as with other destructive methods carries the risk of dyspigmentation and scarring.[99] The dermatologist curettes the clinically apparent tumour with a sharp round instrument, then coagulates the wound bed with electric current to dryness. The eschar is curetted twice more with subsequent electrodessication.

Laser therapy has been demonstrated to be an acceptable alternative to surgery for low-risk lesions on the trunk and extremities for patients with SCC.[100]

Photodynamic therapy, whereby a topical photosensitiser, such as 5-aminolevulinic acid or methyl aminolevulinic acid, induces protoporphyrin accumulation that results in cell death with exposure to visible light, is now widely used and compares well with other methods.[101]​ Studies have shown that the efficacy of photodynamic therapy is similar to, or more effective than other traditional therapies, such as cryotherapy and electrodessication and curettage, with superior cosmetic outcomes.[101][102] Photodynamic therapy is an option for patients with tumours at sites where wound healing is poor/delayed, in the case of multiple and/or large tumours, and where surgery would be difficult or invasive.[103]​​​​

The treatment may result in peeling, crusting, or blistering, and hyperpigmentation may occur on darkly pigmented skin.

Radiotherapy

Radiotherapy is an option for treatment of Bowen's disease, particularly those cases that are deemed unresectable or in patients who are poor surgical candidates. A high rate of tumour control, with minimal morbidity and preservation of normal tissues, has been demonstrated.[104]​ Referral to a radiation oncologist for adjuvant radiotherapy may be indicated for aggressive tumour subtypes.[105][106]

Invasive SCC

Invasive SCC is stratified into low-risk, high-risk, or very-high-risk SCC for local recurrence, metastases, or death from disease.[74]​ Treatment differs based on this stratification.[74]

Low-risk SCC

Patients with low-risk SCC may be treated with electrodessication and curettage, shave removal, standard clinical excision, or Mohs micrographic surgery.[74] Radiotherapy may be used for patients who decline surgery.[74]

Low-risk SCC is defined as:[74]

  • Primary tumour

  • Located on trunk or extremities

  • Size ≤2 cm

  • Clinically well-defined

  • Well or moderately differentiated histology

  • Depth of invasion <2 mm and no invasion beyond subcutaneous fat

Shave removal

Shave removal is an option for some low-risk SCCs. It is most suitable for dermal and epidermal lesions.[74] The tumour is removed by making a transverse, bowl-shaped cut with a scalpel underneath the lesion.[107]

Mohs micrographic surgery

Mohs micrographic surgery is a primary treatment option for low-risk SCC.[74] It may be used for tumours on cosmetically sensitive areas (e.g., face, ears, nose, lips, neck and hands), tumours >2 cm in diameter, and all recurrent tumours, and should be performed by dermatological surgeons who have specialised training and experience in this procedure.[74]

Standard clinical excision

Standard clinical excision is a common therapeutic option for SCC. For the primary treatment of low-risk SCC >2 cm in diameter, 6-mm clinical margins are recommended in the US.[74] UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm for low-risk cutaneous SCC tumour.[90]

Radiotherapy

Radiotherapy is an option for patients with low-risk SCC if they decline surgery; however, it is contraindicated if the patient has genetic conditions predisposing to skin cancer (e.g., basal cell nevus syndrome), and not advisable for patients with with connective tissue diseases such as scleroderma.[74]

High- /very-high-risk SCC

For patients with high- or very-high-risk SCC, where surgery or radiotherapy has a high likelihood of cure, primary treatments may include Mohs micrographic surgery, radiotherapy, or standard clinical excision.[74]

High-risk SCC is defined as:[74]

  • Tumour of any size located on the head, neck, hands, feet, pretibial, and anogenital area

  • Tumour of the trunk of extremities of size 2-4 cm

  • Recurrent tumour

  • Clinically poorly defined

  • Tumour in a person with immunosuppression

  • Tumour at the site of previous radiotherapy or a chronic inflammatory process

  • Presence of neurological symptoms

  • Rapidly growing tumour

  • Depth of invasion 2-6 mm

  • Perineural involvement

  • Acantholytic, adenosquamous, metaplastic, or desmoplastic histological subtype

Very-high-risk SCC is defined as:[74]

  • Tumour size >4 cm (any location)

  • Poorly differentiated

  • Acantholytic, adenosquamous, metaplastic, or desmoplastic histological subtype

  • Depth of invasion >6 mm or invasion beyond subcutaneous fat

  • Tumour cells within the nerve sheath of a nerve lying deeper than the dermis, or measuring ≥0.1 mm

  • Lymphatic or vascular involvement

Standard clinical excision

Standard surgical excision should be offered to people with high and very-high-risk resectable SCC as first-line treatment when Mohs micrographic surgery is not available.[74] In the US, a wider surgical margin, with intraoperative margin control, and post-operative margin assessment, is required for high-risk tumours.[74][88]

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥6 mm or ≥10 mm for high-risk or very-high-risk cutaneous SCC tumour, respectively.[90]

The 5-year cure rate with standard excision for primary SCC is 92%, for recurrent SCC the cure rate is 77%.[108] When performing surgery, peripheral tumour margins should be determined under a bright light with magnification or dermoscopy.

In the UK, ≥1 mm histological clearance of SCC excision from all margins is recommended.[90] This is achieved by excising sufficient peripheral and deep tissues. For mobile lesions, the deep margin should be within the next clear surgical plane. For deeply infiltrating lesions at any site, achieving a clear/uninvolved deep margin may require excision of fascia, muscle, bone, or underlying structures. Where possible, uninvolved margins should be confirmed histologically.[90]

Mohs micrographic surgery

May be used for tumours on cosmetically sensitive areas (e.g., face, ears, nose, lips, neck and hands), tumours >2 cm in diameter, and all recurrent tumours, and should be performed by dermatological surgeons who have specialised training and experience in this procedure.[74]

Mohs surgery provides the highest cure rate for SCC, at >97% for primary tumours. In addition, it allows for optimal tissue sparing, as only the additional areas that carry tumours are removed.[109][110]​​ Local recurrence rates following Mohs have been reported at 16%, with rates of nodal metastasis at 3% for patients with verrucous carcinoma.[111] 

In 2012, the American Academy of Dermatology, the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery published appropriate use criteria for Mohs micrographic surgery, which detail specific indications for performing Mohs surgery.[112]

Radiotherapy

Adjuvant radiotherapy may be indicated for patients with positive or negative margins.[74] For non-surgical candidates, definitive radiotherapy may be considered after discussion with a multi-disciplinary team.[74]

Locally advanced SCC

For patients with locally advanced SCC (primary or recurrent extensive disease where surgery and/or radiotherapy may not result in cure or would possibly produce significant impairment), discussion with a multidisciplinary team, and multimodality treatment including neoadjuvant and adjuvant treatment should be considered.[74] Clinical trials can be considered for both surgical and non-surgical patients.[74]

Neoadjuvant treatment with surgery

Neoadjuvant treatment with cemiplimab, a human monoclonal antibody targeting programmed death receptor-1 (PD-1) on T cells, should be considered for patients with locally advanced SCC if the tumour is growing rapidly, is in-transit metastasis, lymphovascular invasion, or is borderline resectable.[74]

Post neoadjuvant treatment, Mohs micrographic surgery (for cosmetically sensitive tumours or tumours >2 cm) or standard clinical excision (for non-cosmetically sensitive tumours or tumours <2 cm) with wider surgical margins and post-operative margin assessment is recommended.[74]

Radiotherapy and/or systemic therapy

For non-surgical candidates (due to comorbidities, extent of disease, risk of functional or cosmetic defects, or the inability to clear disease with surgery), treatment options include radiotherapy with or without systemic therapy, or systemic therapy alone.[74]

If systemic therapy is given in combination with radiotherapy, cisplatin is the preferred option. If systemic therapy is given alone, preferred regimens include an anti-PD-1 monoclonal antibody, such as cemiplimab or pembrolizumab.[74]

One retrospective, observational, multi-centre study reported that real-world data confirmed the efficacy and safety of cemiplimab for patients with advanced SCC, but that efficacy may differ slightly between European and US regions, which may be associated with different genetic backgrounds.[113]

In Europe and the UK, only cemiplimab is approved for this indication.[114][115]

The management of metastatic disease is beyond the scope of this topic.

Maintenance therapy

Oral retinoids have been shown to prevent recurrence and progression, particularly in immunosuppressed patients (e.g., AIDS, solid organ transplant recipients), and in patients at very high risk for multiple lesions, patients with early-onset aggressive tumours, high sun exposure, and lightly pigmented skin.[42][74][116]

Solid organ transplant recipients

All solid organ transplant recipients should be reviewed by a dermatologist, risk-stratified by key risk factors (e.g., multi-organ transplant, pre-transplant skin cancers, Fitzpatrick skin phototype, demographics, immunosuppression regimen type), and assigned to a screening timeline (every 3 or 6 months or annually).[89]

Consensus-based guidelines make the following recommendations regarding the prevention of squamous cell carcinoma in solid organ transplant recipients:[11] 

  • Cryotherapy for scattered actinic keratosis

  • Biopsy of any lesion suspicious for invasive keratinocyte carcinoma

  • Field therapy with topical fluorouracil for actinic keratoses when grouped in one anatomical area; if actinic keratoses are thick, then field therapy and cryotherapy are recommended

  • Combination lesion-directed and field therapy with fluorouracil for field cancerised skin

  • Acitretin therapy and discussion of immunosuppression reduction for patients who develop multiple skin cancers at a high rate (10 x SCCs per year) or develop high-risk SCC (defined by a tumour with approximately ≥20% risk of nodal metastasis)

Each case should be reviewed on an individual basis by a multi-disciplinary team. For solid organ transplant recipients who are at high risk for SCC, Mohs micrographic surgery is usually recommended rather than standard excision.

For immunosuppressed patients with high-risk features, if Mohs surgery is not performed, margins of 6-10 mm beyond any surrounding erythema and resection into the subcutaneous fat have been recommended by the American Joint Committee on Cancer. High-risk features include invasion into the subcutaneous fat, poor differentiation, perineural invasion, and high-risk anatomical location.[74][89]​​

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