Surgical excision with histologically tumor-free margins is the treatment of choice for resectable cSCC, regardless of tumor location or patient age2–14 (LoE: 2).

Intraoperative margin evaluation using frozen sections may be used in selected cases; however, its high false-negative rate limits its usefulness, and delayed confirmation using paraffin sections is generally preferred.15,16 In addition, several optical techniques—including confocal microscopy, fluorescence imaging, and spectroscopy—are being investigated as tools for intraoperative margin control. However, their clinical application remains limited due to restricted availability and lack of standardization17 (LoE: 5).

These techniques are indicated only in well-defined, low-risk tumors smaller than 1cm in immunocompetent patients. They should be avoided in areas containing hair follicles or when the hypodermis is reached.4,13 They are not recommended in recurrent tumors or tumors considered high risk5,6,9 (LoE: 4).

There are no randomized controlled trials comparing conventional surgery in cSCC.18,19 Current recommendations are derived from retrospective studies and expert consensus (LoE: 5).

Clinical margins should be adapted to the risk of recurrence: in low-risk tumors, most guidelines recommend clinical margins of 4–6mm.4,5 The European consensus specifically recommends 5mm.8 In high- and very-high-risk tumors, margins of 6–10mm or greater are recommended4,13 (LoE: 5).

Histologically negative margins should be achieved through20:

• •

  Margin delineation with optical magnification or dermoscopy.

• •

  Excision reaching at least half of the subcutaneous adipose panniculus.5

• •

  Inclusion of the galea in scalp tumors and assessment of fascia, muscle, or bone in tumors with clinical or radiologic evidence of infiltration.4,21

• •

  En bloc excision with grafting in cancerized fields with multiple cSCCs.8

• •

  Delayed margin confirmation before complex reconstruction when feasible.13

• •

  Coordination with specialized surgical services in anatomically complex areas (orbital region, auricle, oral cavity, cranial vault)3,12 (LoE: 4–5).

In high- and very-high-risk tumors, several guidelines recommend considering surgery with Peripheral and Deep En face Margin Assessment (PDEMA), a term that includes Mohs micrographic surgery (MMS) as the reference technique.

MMS is particularly indicated in high-risk lesions, recurrent tumors, or areas where tissue preservation is critical.5,6,8,13

A meta-analysis estimated recurrence rates of 3.1% for primary cSCC and 10% for recurrent tumors treated with MMS22 (LoE: 2). However, this analysis showed considerable heterogeneity (high I2 in several subanalyses), with large variability in inclusion criteria and follow-up periods, making direct comparison between treatment modalities difficult. Furthermore, selection bias must be considered, since patients treated with MMS often present high- or very-high-risk tumors. Another more recent analysis found no statistically significant differences compared with conventional surgery or radiotherapy23 (LoE: 3).

Some guidelines (BAD,4 German,2 Italian10) restrict MMS to individualized cases following discussion in multidisciplinary teams (MDT). Its effectiveness may be compromised in aggressive histologic variants such as sarcomatoid cSCC, which may be less visible in frozen sections5 (LoE: 4).

In complex reconstructions, delayed MMS or confirmation using paraffin sections may be considered.4 In locations such as the scalp or parotid region, this may not be feasible, and traditional intraoperative margin control may be preferred (LoE: 5).

When no bone involvement is present, supraperiosteal excision of the nail apparatus with 5mm margins followed by grafting is recommended. If bone involvement is present, amputation is indicated24 (LoE: 4).

In cases of positive histologic margins, re-excision is recommended whenever feasible, according to all reviewed guidelines.2–12,14 There is also evidence supporting the use of Mohs micrographic surgery as an alternative treatment for SUSCC, with favorable functional and oncologic outcomes.25

Reconstruction options can be organized according to two conceptual approaches12:

• •

  Reconstructive ladder: proposes progression from simple techniques, prioritizing skin grafting, toward local, regional, distant, or free flaps.

• •

  Reconstructive elevator: proposes directly choosing the option that provides the best functional and esthetic result, without following a fixed sequence.

There are no randomized studies comparing reconstructive methods after cSCC surgery (LoE: 5).

RT is an alternative treatment in patients who are not surgical candidates due to comorbidities, critical anatomical location, or patient preference.4,11,13,26

There are no randomized trials directly comparing primary RT with surgery in terms of local control and survival. However, a meta-analysis including 14 observational studies (1018 patients) treated with RT estimated a pooled local recurrence rate of 6.4%23 (LoE: 2). A systematic review (2021) demonstrated considerable heterogeneity in RT outcomes, partly due to the lack of consensus regarding high-risk definitions and the absence of staging stratification27 (LoE: 5).

Conventional fractionation (2Gy per session) requires achieving a biologically equivalent dose (EQD2) of 65–70Gy to obtain local control rates above 90% in tumors ≥2cm.28 In elderly, frail patients or those with small lesions, hypofractionated schedules (4–7Gy per fraction) may be used.26 If BED≥100Gy is achieved, oncologic and cosmetic outcomes may be comparable29 (LoE: 2). Common regimens include: 50Gy in 15 fractions, and 35Gy in 5 fractions

Single-fraction irradiation is not recommended.

• •

  Fractionation and cosmesis: prolonged fractionation yields better cosmetic results in areas such as the nose, auricle, or lips (LoE: 4).

• •

  PNI: in extensive PNI or involvement of major nerves, the proximal nerve pathway should be irradiated (LoE: 4).

• •

  Re-irradiation: should be considered only in exceptional cases, due to the high risk of complications (LoE: 4).

• •

  Brachytherapy: isotope-based brachytherapy may be useful in well-defined lesions, whereas electronic surface brachytherapy lacks strong evidence (LoE: 4).

• •

  Immunosuppression: in immunosuppressed patients, reduction of conventional immunosuppression and/or incorporation of mTOR inhibitors may be considered in cases of life-threatening cSCC or multiple rapidly evolving tumors (LoE: 5).

  Table 1.

  Principles of radiotherapy treatment.3

  Primary tumor	Examples of dose fractionation and treatment duration
  Tumor diameter<2cm	60–64Gy over 6–7 weeks50–55Gy over 3–4 weeks40Gy over 2 weeks30Gy in 5 fractions over 2–3 weeks
  Tumor diameter ≥2cm, T3/T4, or invasion of bone or deep tissue	60–70Gy over 6–7 weeks45–55Gy over 3–4 weeks
  Postoperative RT (adjuvant)	60–64Gy over 6–7 weeks50Gy over 4 weeks
  Regional disease (nodal)
  After lymph node dissection:
  • Negative margins, no ECE	• 50–60Gy over 5–6 weeks
  • Positive margins or ECE	• 60–66Gy over 6–7 weeks
  Without lymph node dissection:
  • Clinically negative nodes at risk	• 50Gy over 5 weeks
  • Clinically positive nodes	• 60–70Gy over 6–7 weeks
  • Nerves clinically at risk	• 50–60Gy over 5–6 weeks

  RT, radiotherapy; ECE, extracapsular extension.

Clinical scenarios eligible for systemic treatment are described in Table 2:

• •

  lacSCC not amenable to curative local treatment (surgery or radiotherapy) (LoE: 2A).

• •

  mcSCC with confirmed distant metastases (LoE: 2A).

In both contexts, immune checkpoint inhibitors (anti-PD-1) are prioritized, such as cemiplimab and pembrolizumab, which are approved as standard first-line therapy (LoE: 2A).

In immunosuppressed patients, reduction of immunosuppression or switching to mTOR inhibitors may be considered in selected situations (LoE: 4).

When cSCC infiltrates deep structures or arises in locations where local treatment would cause significant morbidity, and the patient is not a candidate for surgery or RT, the following options may be considered:

• •

  Systemic therapy with immune checkpoint inhibitors, particularly anti-PD-1 agents such as cemiplimab or pembrolizumab, approved for lacSCC13 (LoE: 2B).

• •

  In cases of disease progression, intolerance, or contraindication, conventional chemotherapy (cisplatin, 5-fluorouracil, taxanes) may be considered, although responses are generally more limited and toxicity higher8,42 (LoE: 3).

In patients with tumor recurrence or incomplete resection, therapeutic strategies include:

• •

  Wide re-excision, whenever anatomically and functionally feasible3 (LoE: 2B).

• •

  MMS, especially in high-risk areas or when tissue preservation is required24 (LoE: 2B).

• •

  Adjuvant or salvage RT, depending on disease extent and patient condition4,13 (LoE: 2B).

• •

  Close follow-up, in selected cases with minimal residual disease and significant comorbidities13 (LoE: 5).

mcSCC is rare but is associated with a poor prognosis. The therapeutic approach must be adapted to the pattern of dissemination and the patient's overall condition.

• •

  Regional metastases (lymph nodes): In patients with operable disease, regional lymph node dissection is associated with high locoregional control rates. In series with a low nodal tumor burden, a 5-year disease-free survival of 97% has been reported.13,20 Adjuvant RT is indicated in cases of extracapsular extension or multiple nodal involvement (LoE: 2B).

• •

  In-transit metastases: These are rare but indicate very high-risk disease. Treatment should be individualized, combining excision of accessible lesions and/or radiotherapy with anti-PD-1 immunotherapy as the preferred systemic option (LoE: 5).8,13 Participation in clinical trials may be considered in selected cases.

• •

  Distant metastases (visceral or non-regional): The treatment of choice is anti-PD-1 immunotherapy (cemiplimab or pembrolizumab) as first-line therapy, with objective response rates of 44% and durable responses lasting>6 months in 90% of responders12,43 (LoE: 2B).

In patients with progression or contraindications, chemotherapy regimens (cisplatin–5FU, taxanes, or capecitabine) may be considered, although the duration of response is usually limited8,13 (LoE: 3).

In selected cases (e.g., solitary metastases or technically accessible lesions in patients with good performance status), surgical resection with palliative intent may be considered,12 usually combined with radiotherapy (RT).13 However, systematic excision of distant metastases is not recommended, as there is no solid evidence of a survival benefit44 (LoE: 5).

Distant mcSCC (stage IV)

Anti-PD-1 immunotherapy is the first-line treatment in patients with mcSCC who are ineligible for curative surgery or RT13,29,43 (LoE: 2B).

Cemiplimab, approved and reimbursed in Spain since 2023, has shown good tolerability with objective response rates of 44%, including 13% complete responses, with responses maintained for more than 6 months in 90% of responders.43 (see Table 2 and Fig. 1).Pembrolizumab and nivolumab may be used off-label, although data in immunosuppressed patients are lacking8,46–49 (LoE: 5).

Fig. 1.

(A) Treatment of cutaneous squamous cell carcinoma (adapted from Woo et al.48). (B) Therapeutic algorithm for cutaneous squamous cell carcinoma (cSCC) (adapted from Stratigos et al.8). a: For detailed treatment indications and recommendations, see the corresponding section of the European clinical practice Guidelines. b: Locally advanced: by definition, not amenable to curative surgery or curative radiotherapy. c: Lymph node dissection when indicated. d: All systemic treatments are off-label, except the anti-PD-1 agent cemiplimab, which is approved by the FDA and EMA for patients with locally advanced or metastatic cSCC who are ineligible for curative surgery or radiotherapy.

As second-line alternatives when immunotherapy is not feasible, conventional chemotherapy (cisplatin, 5-FU, carboplatin, paclitaxel) or EGFR inhibitors (cetuximab, erlotinib) may be considered, although response rates are limited and toxicity may be substantial31,44 (LoE: 3). Electrochemotherapy may be considered in palliative settings or when no other therapeutic alternatives are available4,31 (LoE: 4).