Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and accounts for approximately 20% of keratinocyte carcinomas.1 In our setting, the estimated incidence is around 38 cases per 100,000 person-years.2

The prognostic relevance of this tumor lies mainly in regional lymphatic recurrences, which occur in approximately 5% of cases, as well as local recurrences, affecting about 2–3% of patients.3,4 These recurrences may lead to death due to locoregional disease progression or the development of systemic metastases.5

Given the significant variability among clinical practice guidelines for the management of cSCC, a comprehensive review of the most relevant guidelines would be advisable. This approach would allow a more complete and unified perspective in the management of this disease.

The aim of this review is to identify and highlight the most relevant recommendations for accurate diagnosis, appropriate staging, and optimal clinical management of cSCC. The clinical recommendations in this manuscript are accompanied by a reference in parentheses indicating the level of evidence (LoE) supporting them, according to the classification of the Oxford Centre for Evidence-Based Medicine (OCEBM, 2011).6 This scale establishes five levels (LoE 1–5), where level 1 corresponds to the highest methodological robustness (meta-analyses, randomized clinical trials) and level 5 corresponds to expert opinion without direct support from studies.

The information and recommendations presented in this document are based on available evidence from relevant publications, as well as consensus and expert experience in the field.7,8 These recommendations were derived from current guidelines indexed in the Medline database, covering the period 2015–2025.9–18

Furthermore, a previously published comparison of national and international clinical practice guidelines regarding treatment recommendations for high-risk and advanced cSCC (2019) was reviewed.19 All clinical practice guidelines used different approaches to classify levels of evidence and express the strength of recommendations, which limits direct comparability among them.

There is no universally accepted staging system for cutaneous squamous cell carcinoma, which complicates comparisons among studies and the standardization of management7,8 (LoE: 3).

The most widely used classifications for risk stratification and staging of cSCC, along with their respective risk criteria, are comparatively summarized in Table 1 (LoE: 2–3).

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  AJCC-8 (American Joint Committee on Cancer, 8th edition, 2017)20:

This classification applies only to tumors of the head and neck.21 Although it introduces improvements over the previous version, it has several important limitations:

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  It does not include tumor differentiation grade.

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  The T4 criterion based on bone invasion is uncommon in clinical practice.

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  Stage III includes highly heterogeneous patients.

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  In-transit metastases are excluded, despite their prognostic relevance.11,22

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  BWH (Brigham and Women's Hospital staging system, 2013)23:

This classification is based on 4 risk factors: Tumor size≥2cm; poor differentiation; perineural invasion (PNI); extension beyond the subcutaneous tissue It is useful for risk categorization, particularly in tumors of the trunk and extremities, but it does not address nodal involvement or metastasis.

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  UICC-8 TNM staging system (Union for International Cancer Control, 8th edition)20,24:

This version runs parallel to AJCC-8,11 but is applicable to any anatomical location. It is recommended by the British Association of Dermatologists (BAD, 2020) and has similar criteria, with broader clinical applicability.

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  Breuninger/Tübingen stagingsystem25:

This German staging system integrates clinical and pathological variables, such as immunosuppression; desmoplasia; and auricular location.26

It is useful for estimating metastatic risk according to tumor thickness.

This system is supported by European consensus guidelines (EADO/EDF/EORTC, 2023)11 and by the German guidelines (2023),17 which include it as a reference for risk stratification.

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  Salamanca stagingsystem27:

This system proposes sub-stratification of stage T3, incorporating: tumor differentiation, PNI, and tumor thickness.

It improves risk homogeneity and stratification, although its use has not yet become widespread.

High-risk cSCC is defined as an invasive lesion without nodal or metastatic involvement (N0M0) that presents features associated with a higher probability of recurrence or metastasis. The systematic identification of these factors helps guide clinical decision-making and should be documented in the pathology report7,10,16,21,23,27 (Fig. 2, LoE: 2).

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  Cellular differentiation: Poorly differentiated or undifferentiated carcinoma carries a higher risk of dissemination.28

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  Depth of vertical invasion: Measured from the intact epidermis to the deepest point of invasion. Extension beyond the subcutaneous tissue or a tumor thickness>6mm is associated with poor prognosis.29

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  PNI: Particularly relevant when the affected nerve is ≥0.1mm in diameter or located in the deep dermis.18 According to AJCC-8/UICC-8, the presence of perineural invasion involving nerves of this caliber alone is sufficient to classify the tumor as T3.

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  Extension beyond subcutaneous fat and bone erosion: These factors are associated with increased risk of recurrence and metastasis according to multiple guidelines.9,11,12

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  Positive histologic margin: Increases the risk of local recurrence and justifies adjuvant radiotherapy.9,11

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  Tumor desmoplasia: This pattern defines the desmoplastic subtype, not yet included in the 2018 WHO classification but considered very high risk in guidelines such as NCCN and the German S3 guidelines because of its high recurrence and metastasis rates.30 Its identification has important prognostic and therapeutic implications.

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  Tumor budding: Defined as the presence of small isolated clusters of tumor cells (<5cells) at the invasive front. It is associated with epithelial–mesenchymal transition and lymph node metastasis.31

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  LVI: The presence of tumor invasion of lymphatic and/or blood vessels is associated with a higher risk of metastatic dissemination.29

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  High-risk histopathologic subtypes of cSCC: Desmoplastic, acantholytic, metaplastic (carcinosarcomatous), and adenosquamous. The desmoplastic subtype is the most frequent and the most aggressive.30

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  Clinical or extrinsic factors15 such as tumor horizontal extension (>20mm), poorly defined tumor borders, history of local recurrence, rapid tumor growth,32 neurological symptoms, previous radiotherapy, immunosuppression, and certain specific anatomical locations (genital area, hands, feet, and “mask areas” of the face: centrofacial region, eyelids, eyebrows, periorbital region, nose, lips, chin, mandible, preauricular and postauricular areas, temples, and auricle).

Fig. 2.

Core features included in the histopathologic report for a diagnosis of cSCC.11

Risk factors should be evaluated cumulatively. The British Association of Dermatologists (BAD) guideline (2020) classifies them as follows:

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  Low risk: No relevant risk factors.

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  High risk: One or more intermediate risk factors.

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  Very high risk: Multiple major risk factors, severe immunosuppression, or critical anatomical location.

Table 2 summarizes the hazard ratios (HR) associated with each variable,8,33-35 and Table 3 provides a risk-stratified clinical management guide, which helps guide treatment planning, follow-up strategies, and the need for multidisciplinary tumor board evaluation.

Routine imaging modalities are not recommended for all patients with cutaneous squamous cell carcinoma, given the generally low risk of metastasis. However, imaging plays a crucial role in patients with high-risk tumors, recurrences, or clinical findings suggestive of deep invasion or dissemination36 (LoE: 3).

Imaging should be individualized according to tumor location, symptoms, prognostic factors, and immune status(LoE: 2). Physical examination, including lymph node palpation, remains essential and should not be replaced by imaging.21

SLNB allows the detection of occult regional metastases in patients without palpable lymphadenopathy, facilitating more accurate prognostic stratification and potentially enabling earlier treatment.7 However, its clinical application in cSCC remains controversial.

It should be considered in patients with very high-risk cSCC (T2b category or higher),40 particularly in the presence of poor differentiation,41 tumor thickness>6mm, size>20mm,13 LVI or PNI,42 or head and neck location (LoE: 3–4).

Among its main limitations are:

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  The lack of a uniform definition of “high risk,” which contributes to variability in sentinel lymph node positivity rates and limits comparability across studies.

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  The scarcity of high-quality evidence, with most data derived from retrospective studies.

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  Although acceptable false-negative rates (3.9%)42 and high negative predictive values (96%)43 have been reported, its prognostic and therapeutic impact remains unclear.

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  Its application may be technically challenging in anatomically complex locations or when complex surgical reconstruction is anticipated.21

Therefore, several clinical practice guidelines consider SLNB an optional procedure with a low level of evidence,10,11,38 which may be considered in well-selected clinical contexts, preferably in immunocompetent patients and following discussion within multidisciplinary tumor boards.9,15–18,44 A recent study observed improved overall survival compared with observation in this patient group,43 although another multicenter study confirmed that this benefit does not extend to immunosuppressed patients.45

In the literature, terms such as advanced cSCC, locally unresectable, aggressive, metastatic, or high-risk cSCC are often used interchangeably, frequently without a precise or homogeneous definition. Cañueto et al.46 proposed a practical classification within the concept of poor-prognosis cSCC (LoE: 3).

cSCC is a common malignancy with a heterogeneous clinical spectrum. Although most cases follow an indolent course, a subset of patients presents a significant risk of recurrence, metastasis, and mortality. Correct identification and documentation of clinical and pathological prognostic factors allow appropriate risk stratification and the planning of individualized management strategies.

Staging systems provide useful reference frameworks, but they have limitations. Therefore, combining additional tools is recommended for a comprehensive evaluation. The cumulative assessment of histologic, clinical, and host-related factors, as recommended by the BAD guideline, helps guide therapeutic decisions and follow-up strategies (LoE: 2–3).

Imaging modalities should be reserved for high-risk tumors, cases with clinical suspicion of deep extension, or immunosuppressed patients (LoE: 2–3). SLNB may be useful in highly selected cases, particularly in immunocompetent patients, although its overall prognostic value remains under evaluation (LoE: 2–3).

In lacSCC or mcSCC, management should be individualized and discussed within multidisciplinary teams. The combination of surgery, radiotherapy, and targeted therapies may improve local control and survival, particularly in aggressive recurrences (LoE: 2–3).

The practical application of these recommendations may optimize the management of cSCC, minimizing sequelae and improving clinical outcomes in patients with this malignancy.

The authors declare that they have no conflict of interest.