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, electrocautery, photodynamic therapy), or pharmacological.[75][87] 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.[88]

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.[43][68]

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.[43][68]

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.[87]

UK guidelines recommend that, prior to performing a diagnostic biopsy or a management procure (e.g., cryotherapy), the following steps are implemented:[87]

  • 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.[87]

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.[75]

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.[89][90][91]

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

All solid organ transplant recipients who present with Bowen's disease should be managed proactively, including field therapy with fluorouracil and low threshold for biopsy, to exclude invasive SCC.[86]

Topical chemotherapy

Topical chemotherapy with fluorouracil-based regimens (e.g., fluorouracil with or without calcipotriol) are preferred.[75] 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.[92][93]​​​ 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 medication 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.[75] 

Local destruction with liquid nitrogen (cryotherapy) is commonly applied.[94][95]​ 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 carries the risk of dyspigmentation and scarring.[96] 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.[97]

Photodynamic therapy

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.[98]​ 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.[98][99] 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.[100]​​​​

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.[101]

Invasive SCC

Patients with low-risk SCC may be treated with electrodessication and curettage, shave removal, standard clinical excision, or Mohs micrographic surgery.[75] Radiotherapy may be used for patients who decline surgery.[75] For patients with high- or very-high-risk SCC, where surgery or radiotherapy has a high likelihood of cure, primary treatments may include standard clinical excision or Mohs micrographic surgery with radiation.[75]

Low-risk SCC is defined as:[75]

  • 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

High-risk SCC is defined as:[75]

  • 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, or metaplastic histological subtype

Very-high-risk SCC is defined as:[75]

  • Tumour size >4 cm (any location)

  • Poorly differentiated or desmoplastic histology

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

In the first instance, standard surgical excision should be offered to people with a resectable SCC.[75] The 5-year cure rate with standard excision for primary SCC is 92%, for recurrent SCC the cure rate is 77%.[102] When performing surgery, peripheral tumour margins should be determined under a bright light with magnification or dermoscopy. 

UK guidelines recommend excision with a clinical peripheral surgical margin of ≥4 mm, ≥6 mm, or ≥10 mm, for low-risk, high-risk, or very-high-risk cutaneous SCC tumour, respectively.[87] In the US, standard excision with a 4- to 6-mm clinical margin is recommended for local low-risk cutaneous SCC; wider surgical margin, with intraoperative margin control, and postoperative margin assessment, is required for high-risk tumours.​[75][85]​​​​

In the UK, ≥1 mm histological clearance of SCC excision from all margins is recommended.[87] 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.[87]

In the US, biopsy at presentation is also recommended with subsequent excision with 4-6 mm clinical margin recommended in first instance for low-risk tumours. US guidance recommends high-risk tumours are assessed on a case by case basis.[75]

Mohs micrographic surgery

May be used for tumours on cosmetically sensitive areas (e.g., face), tumours >2 cm in diameter, and all recurrent tumours.

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.[103][104]​ Local recurrence rates following Mohs have been reported at 16%, with rates of nodal metastasis at 3% for patients with verrucous carcinoma.[105] 

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.[106]

Shave removal

Shave removal is an option for some low-risk SCCs. It is most suitable for dermal and epidermal lesions.[75] The tumour is removed by making a transverse, bowl-shaped cut with a scalpel underneath the lesion.[107]

Radiotherapy

Adjuvant radiotherapy may be indicated for patients with positive or negative margins.[75] For non-surgical candidates, definitive radiotherapy may be considered after discussion with a multi-disciplinary team.[75]

Metastatic SCC

High-risk SCC (i.e., larger and more invasive lesions), perineural invasion, or regional lymph node metastasis requires referral to a multi-disciplinary team (MDT), or an oncologist in the absence of an MDT.[75][87]​​

Treatment may include neoadjuvant treatment, surgery (excision of the tumour and involved lymph nodes), and systemic therapy with or without radiotherapy.[75][108][109]​​

Neoadjuvant treatment

Neoadjuvant treatment with cemiplimab, a human monoclonal antibody targeting programmed death receptor-1 (PD-1) on T cells, may be considered for patients with SCC, after multi-disciplinary discussion, if the tumour has very rapid growth, in-transit metastasis, lymphovascular invasion, is borderline resectable, or surgery alone may not be curative or may result in significant functional limitation.[75] Early phase trials have demonstrated promising results for patients with SCC treated with neoadjuvant cemiplimab.[110][111][112]

Immune checkpoint inhibitors

Treatment with cemiplimab or pembrolizumab, anti-PD-1 monoclonal antibodies, can be used in patients with locally recurrent or metastatic disease not amenable to surgery or radiotherapy.[75] In Europe and the UK, only cemiplimab is approved for this indication.[113][114]​ One retrospective, observational, multicentre 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.[115]

Systemic therapy with or without radiotherapy

For patients with unresectable SCC, radiotherapy with concurrent systemic therapy with cisplatin, carboplatin with or without paclitaxel, or an EGFR inhibitor monoclonal antibody (e.g., cetuximab) may be considered in select cases.[75] A clinical trial should be considered for these patients.[75]

For non-surgical candidates, for whom curable radiotherapy is not feasible, who are not suited to, or have progressed with immune checkpoint inhibitors and clinical trials, systemic therapy alone with carboplatin plus paclitaxel (with or without cetuximab), or an EGFR inhibitor alone (e.g., cetuximab) may be considered.[75] 

Studies have shown efficacy of EGFR inhibitors in decreasing SCCs that are not amenable to surgery, especially of the head and neck.[116][117] Some evidence suggests that EGFR inhibitors may be considered for patients with advanced cSCC who have contraindications to, or who progress on, anti-PD-1 monoclonal antibodies.[118]​​ 

Radiotherapy

Radiotherapy can be used as an adjunct to the surgical treatment of metastatic SCC and has been shown to improve outcomes in patients with positive or negative postoperative margins.[75][108][119]​ There is some evidence to suggest that improved outcomes may be seen in patients with high-risk SCC with concurrent or sequential immune checkpoint inhibition and postoperative radiotherapy.[120]

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 with early-onset aggressive tumours, high sun exposure, and lightly pigmented skin.[43][75][121]

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).[86]

Consensus-based guidelines make the following recommendations regarding the prevention of squamous cell carcinoma in solid organ transplant recipients:[12] 

  • 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.[75][86]​​

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