Approach

The methods used to treat squamous cell carcinoma (SCC) vary depending on tumor type, size and location, patient history, patient comorbidities and immune status, and practitioner. Treatment can be surgical, locally destructive (cryotherapy, electrocautery, photodynamic therapy) or pharmacologic.[73][92] 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.[93]

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 emphasized.[41][67]

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 emphasized.[41][67] 

Pretreatment 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.[92]

UK guidelines recommend that, prior to performing a diagnostic biopsy or a management procure (e.g., cryotherapy), the following steps are implemented:[92]

  • 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.[92]

SCC in situ (Bowen disease)

SCC that is limited to the epidermis may be treated with nonsurgical options such as topical chemotherapy, destructive treatment, and photodynamic therapy.[73] 

Evidence from systematic reviews comparing types of nonexcisional 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.[94][95][96]​​​​

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

All solid organ transplant recipients who present with Bowen disease should be managed proactively, including field therapy with fluorouracil and low threshold for biopsy, to exclude invasive SCC.[84]

Topical chemotherapy

Topical chemotherapy with fluorouracil-based regimens (e.g., fluorouracil with or without calcipotriene) are preferred.[73] 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.[97][98]​​​​ 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 reepithelialize to leave cytologically normal skin.

Destructive therapy

Destructive therapy may include ablative laser vermilionectomy, ablative skin resurfacing, chemical peels, cryotherapy, curettage and electrodesiccation.[73]

Local destruction with liquid nitrogen (cryotherapy) is commonly applied.[99][100]​ 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.[101] The dermatologist curettes the clinically apparent tumor 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.[102]

Photodynamic therapy

Photodynamic therapy, whereby a topical photosensitizer, 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.[103]​ 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.[103][104]​ Photodynamic therapy is an option for patients with tumors at sites where wound healing is poor/delayed, in the case of multiple and/or large tumors, and where surgery would be difficult or invasive.[105]

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

Radiation therapy

Radiation therapy is an option for treatment of Bowen disease, particularly those cases that are deemed unresectable or in patients who are poor surgical candidates. A high rate of tumor control, with minimal morbidity and preservation of normal tissues, has been demonstrated.[106]

Invasive SCC

Patients with low-risk SCC may be treated with electrodessication and curettage, shave removal, standard clinical excision, or Mohs micrographic surgery.[73] Radiation therapy may be used for patients who decline surgery.[73] For patients with high- or very-high-risk SCC, where surgery or radiation therapy has a high likelihood of cure, primary treatments may include standard clinical excision or Mohs micrographic surgery with radiation.[73]

Low-risk SCC is defined as:[73]

  • Primary tumor

  • 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:[73]

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

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

  • Recurrent tumor

  • Clinically poorly defined

  • Tumor in a person with immunosuppression

  • Tumor at the site of previous radiation therapy or a chronic inflammatory process

  • Presence of neurologic symptoms

  • Rapidly growing tumor

  • Depth of invasion 2-6 mm

  • Perineural involvement

  • Acantholytic, adenosquamous, or metaplastic histologic subtype

Very-high-risk SCC is defined as:[73]

  • Tumor size >4 cm (any location)

  • Poorly differentiated or desmoplastic histology

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

  • Tumor 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.[73] The 5-year cure rate with standard excision for primary SCC is 92%, for recurrent SCC the cure rate is 77%.[107] When performing surgery, peripheral tumor 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 tumor, respectively.[92] 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 tumors.[73][83]​​​​​ 

In the UK, ≥1 mm histologic clearance of SCC excision from all margins is recommended.[92] 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.[92]

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 tumors. US guidance recommends high-risk tumors are assessed on a case by case basis.[73]

Mohs micrographic surgery

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

Mohs surgery provides the highest cure rate for SCC, at >97% for primary tumors. In addition, it allows for optimal tissue sparing, as only the additional areas that carry tumors are removed.[108][109]​​ Local recurrence rates following Mohs have been reported at 16%, with rates of nodal metastasis at 3% for patients with verrucous carcinoma.[110]​ 

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.[111]

Shave removal

Shave removal is an option for some low-risk SCCs. It is most suitable for dermal and epidermal lesions.[73] The tumor is removed by making a transverse, bowl-shaped cut with a scalpel underneath the lesion.[112]

Radiation therapy

Adjuvant radiation therapy may be indicated for patients with positive or negative margins.[73] For nonsurgical candidates, definitive radiation therapy may be considered after discussion with a multidisciplinary team.[73]

Metastatic SCC

High-risk SCC (i.e., larger and more invasive lesions), perineural invasion, or regional lymph node metastasis requires referral to a multidisciplinary team (MDT), or an oncologist in the absence of an MDT.[73][92]​​

Treatment may include neoadjuvant treatment, surgery (excision of the tumor and involved lymph nodes), and systemic therapy with or without radiation therapy.[73][113][114]​​

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 multidisciplinary discussion, if the tumor 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.[73]  Early phase trials have demonstrated promising results for patients with SCC treated with neoadjuvant cemiplimab.[115][116][117]

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 radiation therapy.[73] In Europe and the UK, only cemiplimab is approved for this indication.[118][119]​​ One retrospective, observational, multicenter 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.[120] 

Systemic therapy with or without radiation therapy

For patients with unresectable SCC, radiation therapy 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.[73] A clinical trial should be considered for these patients.[73]

For nonsurgical candidates, for whom curable radiation therapy 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.[73]

Studies have shown efficacy of EGFR inhibitors in decreasing SCCs that are not amenable to surgery, especially of the head and neck.[121][122] 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.[123]

Radiation therapy

Radiation therapy can be used as an adjunct to the surgical treatment of metastatic SCC and has been shown to improve outcomesin patients with positive or negative postoperative margins.[73][113]​​[124]​​​​ 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 radiation therapy.[125]

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 tumors, high sun exposure, and lightly pigmented skin.[41][73][126]

Solid organ transplant recipients

All solid organ transplant recipients should be reviewed by a dermatologist, risk-stratified by key risk factors (e.g., multiorgan transplant, pretransplant skin cancers, Fitzpatrick skin phototype, demographics, immunosuppression regimen type), and assigned to a screening timeline (every 3 or 6 months or annually).[84]

Consensus-based guidelines make the following recommendations regarding the prevention of squamous cell carcinoma in solid organ transplant recipients:[15] 

  • 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 cancerized 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 tumor with approximately ≥20% risk of nodal metastasis).

Each case should be reviewed on an individual basis by a multidisciplinary 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.[73][84]​​

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