The two subtypes of cutaneous neoplasms are melanoma and nonmelanoma skin malignancies. Skin malignancies other than melanoma include sarcoma, adnexal tumors, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC) and Merkel cell carcinoma (1). cSCC, melanoma and other types of cancer often spread to regional and distant sites, which can markedly affect the clinical course of the disease and patient prognosis (2). BCC normally exhibits localized, slow growth, but rarely metastasizes. The head and neck region, where >50% of newly diagnosed cSCC lesions are located, presents unique challenges in surgical treatment (3). In addition, the chances of survival of patients with cSCC are reduced by localized and/or distant metastases, and the disease is responsible for the death of 2% of patients annually worldwide. While most nonmelanoma malignancies are BCC (70-80%), cSCC accounts for ~20% of all reported cases (4). As sun exposure is a significant risk factor for cSCC, the ear, cheek, lip and scalp are common sites of occurrence. cSCC is classified into low-risk and high-risk tumors based on prognostic variables, including human papillomavirus infection, smoking and location (specifically the scalp), and patients with high-risk cSCC require more intensive treatment and follow-up. However, these recommendations do not consider the age of the patient at diagnosis, and assume that the tumor features are identical in both adult and elderly individuals (5).

Uncontrolled proliferation of atypical keratinocytes, a primary cell type found in the epidermis, is responsible for the development of cSCC (6). A substantial increase in the incidence of cSCC has been reported in the literature. Longitudinal studies conducted in Canada and Australia over the past 30 years have revealed a 50-300% increase in the prevalence of primary cSCC (7). BCC generally experiences gradual confined growth and hardly metastasizes; by contrast, cSCC, melanoma and other types of cancer often spread to both nearby and distant locations, which can have an impact on the clinical course of the disease and the well-being of the patients (8). The early detection of individuals who are more likely to develop metastatic disease would justify the need for surveillance (9). Currently, to the best of our knowledge, there are no indicators of metastasis in cSCC other than conventional histopathological examination. High-risk clinicopathological characteristics of cSCC metastasis include immunosuppression, poor histological differentiation, perineural invasion (PNI), lymphovascular invasion, tumor size >2 cm, depth of invasion >6 mm, and the main location being the scalp, ear or lip (10). Consensus is currently lacking on the definition for high-risk conditions or the ideal cSCC therapy. A previous study reported that 20-40% of head and neck cutaneous neoplasms disseminate to lymph nodes outside of clinically expected levels (11). In locating interval nodes, preoperative lymphoscintigraphy or single photon emission computed tomography is recommended to aid sentinel lymph node biopsy (SLNB) in the head and neck or trunk areas (12). In clinical practice, nodal metastasis of head and neck cSCC (HNcSCC) most often occurs in the parotid glands. The anterior and posterior skin zones are generally categorized according to the drainage pattern in the head and neck area, with a hypothesized lymphatic watershed area between them (13). The occipital, postauricular, cervical level V and supraclavicular fossa are the drainage sites for the posterior part of the head and neck (14), and the parotid and preauricular nodes, as well as the anterior cervical nodes, are the drainage sites of the anterior head and neck areas (15).

Tumor characteristics and patient considerations influence treatment selection and prognosis (52). Prior to the development of immunotherapy, cytotoxic platinum-based chemotherapy and targeted therapy, which inhibits the epidermal growth factor receptor (EGFR), were the only systemic treatments available for HNcSCC (53). With a 50% response rate, good tolerability and long-lasting disease control, immunotherapy has radically transformed the management of advanced and metastatic cSCC (54). A high level of complete response, as well as lasting, meaningful clinical response, has been seen in patients with advanced cSCC. Numerous clinical trials (such as NCT04154943, NCT03916627, NCT03969004 and NCT03833167) (Table I) examining the use of these novel therapies in clinical settings highlight the need to thoroughly define the epidemiology and morbidity of cSCC to understand how such treatments revolutionize patient outcomes (55). The United States Food and Drug Administration approved cemiplimab in 2018 as the first immunotherapy drug for the treatment of metastatic or locally advanced cSCC unresponsive to curative therapy (56). The reaction of the immune system to cancer cells is considerably regulated by immune checkpoint proteins (57). Two steps are essential for T-cell activation: i) Peptides must be recognized by the T-cell receptor; ii) partner proteins on tumor cells must interact with coregulatory proteins (immune checkpoints) on T cells (58). When activated, immune checkpoints can have either stimulatory or inhibitory effects on the immune system (59). Immune checkpoints facilitate an appropriate immune response while preventing the death of healthy tissues and immune hyperactivation, as seen in autoimmune disorders (60). A compromised immune system promotes mutations; therefore, subsets of cancer cells are able to evade immune detection owing to the compromised antitumor response of the immune system (61). This evasion is referred to as the escape mode, which permits unregulated tumor growth and progression (62). Cemiplimab is a monoclonal antibody that targets PD-1. With a discontinuation rate of just 7% and an adverse event rate comparable to that of other anti-PD-1 medications, cemiplimab is considered to have an acceptable safety profile (63). Pembrolizumab is another immunotherapy agent, which is permitted for use in individuals with locally advanced, metastatic or recurrent HNcSCC who are not candidates for radiation therapy or surgery. This drug is well tolerated and has yielded good results (64). Cutaneous immune-related adverse symptoms, including the rare Stevens-Johnson syndrome/toxic epidermal necrolysis (65), are primarily managed with glucocorticoids; however, the prolonged use of glucocorticoids can lead to various side effects and reduce antitumor activity. Therefore, identifying a safe and efficient approach to manage cutaneous immune-related adverse reactions is critical, including conventional and alternative therapies (66). For example, Feiji Recipe, a Chinese herbal compound, is known to exert anticancer effects by stabilizing the lesions through the modulation of T-cell immunity in patients with lung cancer. The molecular action of this herb is to restore T-cell activity by interfering with indoleamine-2,3-dioxygenase (67).

Platinum drugs (cisplatin or carboplatin), 5-fluorouracil, bleomycin, doxorubicin, methotrexate and taxanes are examples of the chemotherapeutics explored so far in treating cSCC (49). Platinum agents, either in isolation or in combination, have been the most commonly employed therapeutic approaches. Data on the effectiveness of chemotherapy have generally been obtained only from small observational studies with a confined range of results (68). Poor efficacy, brief duration of the response (non-curative) and increased toxicity are the limitations of chemotherapy, which is a significant treatment challenge for elderly patients or those with several comorbidities (69). Numerous medications, such as cisplatin, target cancer cells by attaching to their DNA; however, once the DNA is broken, cells can use various methods to repair the lesions and stimulate resistance mechanisms (70). Table II summarizes the most frequent chemotherapeutic drugs used to treat cSCC, including their mechanisms, results and potential adverse events. The unique binding site of the drug on the target molecule must be precisely identified to facilitate drug-target interaction. Intrinsic resistance can be caused by the presence of a mutation, low expression or the absence of the drug-metabolizing enzyme-binding site before treatment (71). Moreover, cells may try to repair the harm or reverse the loss by upregulating the production of repair enzymes, reducing cell death, which results in the development of induced resistance with changes in the cell microenvironment (72). In response, there are higher drug release rates and increased capacity for DNA repair of the cells. Hence, with promising results and perspectives, we accept the recommendation that patients who are considered ineligible or exhibit disease progression following immunotherapy should undergo cytotoxic chemotherapy. Fig. 1 illustrates the ongoing cycle of drug resistance within the tumor microenvironment.

The radiotherapy planning and treatment process is extensive and involves several procedures (73), such as patient consultation and the interpretation of diagnostic imaging (74). Currently, there is no consensus regarding the methods used to treat locally advanced HNcSCC. Based on the limited retrospective studies (75,76) that have thus far been reported, surgical resection is often followed by adjuvant therapy in patients with HNcSCC (77). The highest risk of recurrence has been identified in patients with positive margins, substantial PNI or significant nerve involvement (78). To maximize locoregional control, postoperative radiation treatment has long been utilized to treat patients with locally advanced cancer (e.g., T3/T4, lymph node-positive and PNI) (79) and has demonstrated high control rates in various retrospective studies (80-82). With the aid of intensity-modulated radiotherapy, steep dose gradients can be produced even in target volumes with a concave shape by combining irradiation beams with nonuniform fluence intensities. To increase the therapeutic index, the ultimate goal is to precisely administer the radiation dose to the target site, maximizing the tumor dose and limiting the damage to vulnerable nearby organs (83). According to a recent study, the 2-year progression-free survival rates for intermediate-risk patients randomly assigned to receive 50 and 60 Gy adjuvant radiotherapy were 95.0 and 95.9%, respectively (84). This finding supports the use of de-escalated adjuvant therapy for patients who have undergone surgery (85). In general, radiotherapy is reasonably well tolerated. Acute and delayed potential radiotherapy-related toxicities are those that occur within the first 6 months post-treatment and beyond (86). Skin reactions, from redness to ulceration, can be the first sign of acute toxicity (87). Delayed toxicities are more commonly encountered at higher doses and can appear months to years after radiotherapy. Alterations in skin pigmentation, necrosis, atrophy, fibrosis and secondary malignancies are examples of delayed toxicities (Table III) (88).

Depth of invasion (DOI) of a tumor, assessed in Breslow thickness or histological depth, has been linked to metastasis (89). Patients with malignancies with a DOI of >2 mm experience a greater relative risk, whereas no metastases have been identified for superficial tumors with DOIs <2 mm (90). In addition, tumor invasion beyond the subcutaneous fat layer has been linked to nodal metastasis (subhazard ratio 7.2) (91). Wermker et al established an indicator model based on tumor depth, cartilage invasion, recurrence number and grade, which identified patients with cSCC of the ear who may benefit from neck lymph node dissection. Large tumors are associated with lymph node metastasis and low survival rates. Lymph node metastasis, whether diagnosed at the onset or after therapy, appears to be related to 5-year death rates; lymph node involvement raises the risk of recurrence by 51% and reduces the 3-year overall survival rate to 52% despite second-line therapy (92). Considering all risk factors for metastasis in cSCC is crucial for the earliest detection of patients who require aggressive, multiple forms of therapy.

The use of photoimmunotherapy to treat patients with cSCC is currently being investigated in two trials, NCT05220748(93) and NCT04305795(94). An antibody-dye conjugate is injected, which is subsequently activated using a certain wavelength of light. RM-1995 is an antibody that specifically targets CD25, a receptor more often expressed by regulatory T cells than other cell types (95). This treatment method targets regulatory T cells within tumors (96) and becomes activated when exposed to red light, resulting in increased anticancer immune response. RM-1995 is administered both alone and in combination with pembrolizumab. Notably, ASP-1929 is an EGFR antibody that can be triggered by red light, and cemiplimab and ASP-1929 can be administered simultaneously (97). Another trial, NCT04160065, is examining the injection of an intratumoral vaccine that expresses the plasmid DNA IFX-Hu2.0(98). As a result, a streptococcal membrane protein is expressed within the lesion, which stimulates the immune system and creates an ideal environment for immune checkpoint inhibitor therapy. A total of 20 patients with advanced nonmelanoma skin malignancies are to be enrolled in phase I research (which is currently underway) (99).

Upon being injected into tumors, oncolytic viruses stimulate the human body to evoke both local and systemic anticancer responses (100). Locally, the injected tumor is infected by oncolytic viruses that cause tumor lysis and cell death (101). In addition, oncolytic viruses can exert crucial antineoplastic effects and support the migration of tumor-specific T lymphocytes to uninjected tumor cells (102). Finally, increased interferon-γ signaling results in the overexpression of PD-1 on host T cells and PD-L1 on tumor cells (103), which, when targeted by PD-1 inhibitors exerts a strong antitumor impact (104). RP1 is a genetically altered herpes simplex oncolytic virus (105). According to Liu et al (106), patients with HNcSCC and other tumor types experienced a complete remission rate that approached 50% in the phase I/II IGNYTE trial upon the administration of RP1 monotherapy or in combination with nivolumab. The use of RP1 both alone and in combination with cemiplimab in patients with advanced cSCC is currently being studied in a phase II trial, NCT04050436(107). In addition, RP1 is being assessed in a phase IB/II trial involving solid organ transplant recipients with advanced cutaneous malignancies, including cSCC (108).

According to previous research, a number of patients with HNcSCC tend to be frail, and such patients are highly likely to experience postoperative challenges (109). Reducing the length and scope of the procedure could decrease the complication rate and adverse long-term effects, as general anesthesia and therapeutic intensity have been shown to be predictors of postoperative complications (110). Although SLNB has been demonstrated to be viable, it has minimal predictive use for this condition (111). The SLN status in relation to the outcomes of HNcSCC has a low predictive value due to various reasons. First, the anatomy of the lymphatic network is complex, and involves bilateral or contralateral drainage in up to 10% of patients (112); therefore, the surgeon must detect SLNs with a high precision (113). Fibrosis from prior tumor surgery and trauma itself can both alter and obstruct the natural lymphatic pathways (114). Several studies have reported that cSCC can perineurally invade the surrounding soft tissues (115,116); this finding suggests that in contrast to, for example, melanoma, the processes of cancer spread depend less on the lymphatic system and have multiple patterns of invasion (117). Often, during surgery for cSCC, a tumor that travels via a cranial nerve to the base of the skull is identified (118), which may be treated via radiotherapy (119). On pretreatment radiographs, a tumor that has spread to the brain via the cranial foramen may often be visible; nevertheless, it is important to highlight that individuals with such tumors are unlikely to be cured and that such tumors are no longer amenable to surgery (120). Aggressive surgery, with or without adjuvant radiotherapy, has been shown to be successful in limiting the degree of tumor involvement (121) and in maximizing disease-free survival in patients with highly advanced cSCC with PNI (122). A pooled average local recurrence rate of 6.4% after radiotherapy was reported in a 2012 meta-analysis of 14 retrospective studies, which amounted to 1,018 primary cSCC cases (123). It may be hypothesized that understanding of the fundamental biology of SCC and BCC represents the future of head and neck cancer treatment standards, with the potential to increase survival rates while limiting local adverse events. Using current options with newer, experimental treatments may not only increase the quality of life for these patients, but also increase their life expectancy. Although immunotherapy has a significant potential in cancer treatment as a single medication, multimodal approaches with more than one focus seem to be more effective.

In conclusion, patients with localized metastatic disease exhibit treatment-elevated morbidity and decreased survival rates. The present study indicated that identifying patients with high-risk disease is vital for providing the best possible care, including access to drug trials. As molecular and genetic biomarkers become more reliable and standardized, it is suggested that they should also be included in patient risk stratification, so that physicians can provide personalized therapies and precision surgery to improve patient outcomes.