Current prognostic indicators for recurrence, pivotal in determining the appropriate course of definitive or adjuvant therapies, are grounded in clinicopathologic attributes expounded within solitary-center or expansive clinical investigations, or consensus conventions. These indicators have been formulated by assimilating local staging, site, depth, and pathological attributes.

Surgery holds its place as the foremost therapeutic intervention in addressing cSCC. Main treatment objectives revolve around complete elimination of the tumor while preserving functional integrity and favorable cosmetic outcomes. In scenarios where surgical intervention is unfeasible, such as cases involving locally advanced disease or elderly patients with concurrent medical conditions, radiotherapy (RT) is the primary therapeutic strategy [26]. Prevailing clinical guidelines provide clear and definitive recommendations regarding primary treatments for high-risk cSCC. The objective of surgical excision is to achieve both clinical and microscopic comprehensive resection (R0 surgery), securing unambiguous (negative) histological margins [27].

In accordance with the European guidelines, a clinical safety margin of 5 mm is advised for lesions categorized as low-risk [27]. On the other hand, cases of high-risk cSCC call for a clinical safety margin ranging between 6 to 10 mm, or alternatively, an approach involving micrographically controlled surgery (MCS). MCS entails surgical excision followed by horizontal section processing of skin tissue, subjected to microscopic examination. This iterative process continues until the absence of cancerous cells is ascertained at the surgical margins, based on anatomical documentation. Within the realm of MCS, methodologies like Mohs micrographic surgery (MMS) and 3D histology are embraced, utilizing frozen sections and paraffin sections respectively, to analyze tissue specimens [27]).

Chung et al. investigated the occurrence and risk factors associated with histopathologic upgrading of cSCC during MMS [28]. The term "upgrade" was defined as the identification of a less advanced degree of differentiation (poor or moderate) and/or the presence of bone or perineural invasion during MMS, which had not been initially detected in the histopathological evaluation of the initial biopsy. Among the 1558 tumors that underwent examination, 115 (7.4%) were subjected to upgrading during MMS. Through a comprehensive analysis involving multivariate logistic regression, it was found that male gender, prior field treatment, location on the ear/lip, rapid cSCC growth, and a tumor diameter exceeding ≥ 2 cm were all notable predictors of tumor upgrading. Those tumors that experienced upgrading appeared to necessitate more than three stages of MMS for adequate clearance, intricate closure methods such as flaps or grafts, or referral-based repairs.

Soleymani et al., observed that the cohort of high-risk cSCC cases treated with MMS exhibited decreased incidences of local recurrence (LR), nodal metastasis (NM), and disease-specific death (DSD) in comparison to historical reference controls [29]. This assessment was conducted by utilizing both the staging systems of BWH and the AJCC 8th edition. The study also revealed that MMS confers a survival advantage specific to the disease over the historical approach of wide local excision in the management of high-risk tumors. Furthermore, the enhancement of local tumor control with MMS appears to contribute to a reduction in the occurrence of regional metastatic disease, and it is plausible that MMS might confer a survival benefit even for patients who develop regional metastases [29]. An extensive meta-analysis by Fraga et al. underscores a diminished rate of locoregional recurrence associated with complete margin assessment in comparison to sectional assessment [30]. The discrepancy is particularly pronounced in cases of high-risk keratinocyte carcinomas and cSCC characterized by PNI. Therefore, the strategy of peripheral and deep end face margin assessment (PDEMA), advocates for excision in combination with meticulous histological evaluation of the peripheral and deep excision surgical margins, positioning it as the standardized therapeutic protocol.

While varying guidelines put forth differing recommendations concerning safety margin dimensions for high-risk cSCC, a consensus exists that wider margins are imperative for high-risk cases as opposed to low-risk tumors. Recommendations regarding margin sizes are primarily rooted in expert consensus, retrospective studies, and observational analyses. The overarching goal remains the achievement of negative surgical margins whenever feasible, with the consideration of re-excision in cases of positive margins, as deemed practicable.

Adjuvant radiotherapy (ART) has been regarded as a treatment option for patients with high-risk cSCC (59). Figure 1 summarize the recommendations on ART in current guidelines. Nevertheless, the advantages of ART, particularly after achieving clear surgical margins, remain contentious and have not been conclusively assessed. Thus, substantial variation in the application of ART for cSCC. Certain studies reported in this analysis did not demonstrate a significant difference in survival outcomes between surgery and a combined approach involving surgery and ART (Table 2).

Current adjuvant radiotherapy recommendations for high-risk cutaneous squamous cell cancer. Created with BioRender.com

In the study by Ebrahimi et al., the regional control rate stood at 91% vs. 87% (p = 0.054), and the average number of adverse features was 1.1 vs. 1.3 in the surgery-only and combined therapy groups, respectively [31]. However, this study revealed that 80% of patients with close margins, extracapsular spread (ECS), or other risk factors received ART, whereas over half of those treated solely with surgery did not have ECS. In other studies, ART was administered to patients with regional metastasis; this context potentially contributed to the absence of significant outcomes in these studies, given the potentially worse patient condition in the ART group [32, 33]. The pooled analysis conducted by Zhang et al., suggests potential benefits of ART in reducing recurrence rates and enhancing survival, both in the general population and in the subgroup with clear surgical margins [34]. Notably, studies demonstrating a survival benefit after ART often featured metastatic cSCC involving the parotid gland or regional lymph nodes, a common risk factor for significantly worse survival.

A meta-analysis by Kim et al. investigated the comparative risk of unfavorable outcomes among patients subjected to surgical intervention as opposed to those receiving both surgical treatment and ART [35]. The study encompassed a compilation of thirty-three investigations, enlisting a collective cohort of 3867 cases featuring high-risk cSCCs. They showed that for individuals harboring high-risk cSCCs who underwent margin-negative resections, the distinction in unfavorable outcomes between those subjected to surgical procedures and those receiving surgery with adjunctive radiotherapy was not different. However, retrospective analyses have underscored the efficacy of ART in cSCC patients with negative surgical margins, especially in cases featuring T3 stage, PNI > 0.1 mm, and poor histopathologic differentiation. Particularly, results hint at a potential reduction in the risk of local recurrence when combining surgery and ART (2.8%) compared to surgery alone (27.9%) in cases where PNI is the primary high-risk factor, although this difference did not reach statistical significance. To note that most studies that included cases with PNI focused on instances of large-caliber nerve invasion or cases with clinical and/or radiologic evidence of PNI. However, while a correlation between vascular involvement and positive surgical margins has been established as a risk factor for increased distant or regional recurrence, and a beneficial role of ART is suggested, data regarding survival outcomes linked to PNI nerve diameters or numbers are scarce and conflicting.

Stevenson et al. investigated individuals who had been diagnosed with histologically confirmed cSCC and evidence of PNI [36]. All patients were evaluated for eligibility to supplementary radiotherapy based on the identification of PNI characterized by large-caliber dimensions (≥ 0.1 mm in diameter), or PNI characterized by small-caliber dimensions (< 0.1 mm), coupled with other high-risk features such as dimensions exceeding 2 cm, limited differentiation, incursion surpassing subcutaneous adipose tissue, immunosuppression, and localization to the craniofacial region. Overall, 31 patients underwent MMS, achieving negative margins in all instances. Although the radiation oncologist recommended adjuvant radiotherapy for all patients, merely 15 individuals (48.4%) underwent the full course of treatment. The tolerability of ART was observed to be favorable, with 6 patients developing mild dermatitis. Over the span of a 5-year follow-up, no instances of local recurrence were recorded. A notable difference emerged between the two groups concerning nodal metastasis: all 5 patients who developed nodal metastases did not receive ART, whereas none among those treated with combined therapy exhibited nodal metastasis (p = 0.02). The 5-year period prognosis for DFS was different between individuals subjected (100% 95% CI, 100%-100%) or not subjected to ART (68.8%, 95% CI, 60.9%-76.7%). Large-diameter PNI was reported by 80% patients with nodal metastasis. However, one patient who underwent only surgical intervention and subsequently manifested nodal metastasis exhibited perineural invasion of smaller dimensions. These findings emphasize the plausible utility of ART for both cases involving large-caliber PNI and instances of small-caliber PNI associated with other high-risk attributes. While it was previously held that the caliber extent of involved nerve fibers could influence outcome, recent insights reveal that even instances of small-caliber PNI entail a fourfold increase in the likelihood of nodal metastasis if coupled with two additional risk factors The risk undergoes a further 14-fold increase if associates with three other risk factors [37].

Jambusaria-Pahlajani et al. compared the outcomes of high-risk SCC treated with surgical monotherapy to those subjected to a combination of surgery and ART [38]. Among the 2,449 instances of high-risk SCC considered, a subset of 91 cases was managed with surgery and ART. Within the 74 cases with PNI, outcomes encompassing local recurrence, distant metastasis, and disease-specific mortality were not different between the surgery and surgey plus ART. Analyzing the subset of 943 high-risk SCC cases featuring well-defined surgical margins, the risks associated with local recurrence, regional metastasis, distant metastasis, and disease-specific mortality were quantified at 5%, 5%, 1%, and 1%, respectively. Favorable therapeutic outcomes were reported for high-risk cutaneous SCC cases when clear surgical margins were achieved. Current available data do not offer specific high-risk features of patients who may benefit by ART. The extent of nerve involvement was found to impact on outcomes, as larger nerve involvement (diameters ≥ 0.1 mm) contributed to a worsened prognosis [38].

In another study focusing on PNI in cSCC conducted by Garcia-Serra and colleagues, it was determined that among 76 patients with advanced PNI, as defined by clinical symptoms or radiological findings, the risk of local recurrence was more than doubled (45%) when contrasted with 59 patients exhibiting only microscopic PNI (13%) [39]. Notably, this trend held true irrespective of the status of surgical margins. For cases featuring solely microscopic invasion, nearly all instances of recurrence were observed in cases with positive surgical margins. This underscores the significance of achieving clear surgical margins in yielding positive outcomes for microscopic PNI. However, this study does not provide a conclusive assessment of whether adjuvant radiotherapy further improves outcomes in cases with clear surgical margins, as all patients in this study received such treatment. Conversely, instances characterized by advanced PNI exhibited a substantial likelihood of recurrence even in the presence of clear surgical margins. This underscores the challenge of effectively managing advanced PNI solely through surgical intervention. Consequently, ART is generally recommended in cases featuring symptomatic or radiologically confirmed PNI.

In their most recent work, Canueto et al. conducted a comprehensive assessment of ART in cSCC with PNI. The primary objective was to identify the specific patient signatures that may better benefit of a specific therapeutic approach [40]. The retrospective analysis of a multicenter cohort comprising 110 instances of cSCC with PNI investigated the categories of PNI associated with unfavorable outcomes, evaluated the efficacy of ART in distinct subsets of cSCC with PNI, and examined the utility of ART with respect of the status of surgical margins (clear or positive). The outcomes showed that ART was superior to a strategy of observation alone, particularly for cases of cSCC with PNI and positive margins post-surgery. In patients undergoing observation alone the risk of adverse outcome events increased by a factor of 2.43 times (p = 0.025). This effect was particularly evident in cases withy positive margins and PNI measuring ≥ 0.1 mm (the likelihood of a negative prognosis increased eightfold, p = 0.0065). Notably, the implementation of ART yielded significant enhancements in long-term outcomes for patients afflicted with cSCC featuring PNI and positive margins following surgical intervention. However, the benefit of ART was less pronounced for cases with clear margins, particularly those with PNI in small-caliber nerves.

Although ART can lead to improved survival outcomes, it is also associated with increased post-treatment complications, such as skin erythema, mucositis, recurrent cellulitis, chronic pain, and others, severely impacting the patients' quality of life, or contributing to disease-specific death. Further prospective comparative studies are required to comprehensively evaluate the benefit and the risks of ART for cSCC patients.