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Metastatic patterns and treatment options for head and neck cutaneous squamous cell carcinoma (Review)

  • Authors:
    • Doriana Iancu
    • Ana Fulga
    • Doina Vesa
    • Andrei Zenovia
    • Iuliu Fulga
    • Mihaela Ionela Sarbu
    • Alin Laurentiu Tatu
  • View Affiliations

  • Published online on: April 24, 2024
  • Article Number: 40
  • Copyright: © Iancu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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According to current predictions, one‑fifth of all Americans will develop skin cancer during their lifetime. Cutaneous squamous cell carcinoma (cSCC) most commonly occurs in the head and neck region, which is the area of the body with the highest level of sun exposure. High‑risk head and neck cSCC (HNcSCC) is a broad category with numerous high‑risk factors that are associated with unfavorable results. In cSCC staging systems, clinical and tumor traits that are likely to result in poor outcomes are identified. Metastasis occurs in ~2.5% of patients with cSCC, most often in the local lymph nodes, and there is some indication that lymph node metastasis has a distinct pattern based on the tumor site. Current findings on tumor molecular targets have suggested the use of systemic treatments, particularly immunotherapy (such as cemiplimab, pembrolizumab and nivolumab), over radiotherapy or chemotherapy for this type of metastasis. However, when used simultaneously with immunotherapy, radiotherapy may be beneficial in the treatment of metastatic HNcSCC by improving the efficacy of immunotherapy. The present review aims to assess the existing literature on metastatic HNcSCC pathways and treatment options, in order to define current and future directions. Notably, there is an urgent need to identify patients who may benefit from local or systemic cancer treatments. The treatment of lymph node metastasis presents a therapeutic challenge and requires comprehensive management.

1. Introduction

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).

2. Clinicopathological features

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).

3. Metastasis

Nodal metastasis

Tumor staging systems have been devised to predict the risk of nodal metastasis and death. Significant research has been performed to characterize the clinical and histopathological characteristics of the subset of cSCC at a high risk for nodal metastasis (16). In nodal metastasis, both the size and number of lymph nodes involved influence the probability of disease-specific death (17). The identification of a low-risk population and the high cure rates for early nodal disease imply that earlier detection of nodal metastases may simplify the treatment and enhance the outcomes. Furthermore, a state of immunosuppression has been hypothesized to lower the overall survival rate and increase the likelihood of metastasis (18). The value of radiological imaging resides in its ability to detect abnormally sized lymph nodes, most likely as a result of tumor infiltration, in individuals with no clinical evidence of lymphadenopathy (19). Clinically palpable nodes necessitate fine needle aspiration or biopsy to confirm the diagnosis, CT or ultrasound for preoperative staging, and subsequently, regional lymph node dissection. There is increasing evidence that SLNB for cSCC is a promising method to identify microscopic metastases (20). When used for diagnosing head and neck tumors, SLNB is usually safe, with a 5.1% combined risk of hematoma, seroma and infection. Patients with a positive SLN have a significantly higher disease-specific death rate than those with a negative SLN, which suggests that SLNB could be used as a prognostic indicator (21). False positives, which could lead to further excessive procedures, and false negatives, which result from failed attempts to detect micrometastases, are two examples of the limitations of SLNB (22).

In-transit metastases

SCC in-transit metastases are described as tumor foci that have spread from the main tumor to the next local lymph node basin, and typically manifest as subcutaneous or dermal nodules (23). In immunocompromised patients, such as organ transplant recipients, these metastases develop from aggressive original tumors (SCC stage ≥T2). The initial tumor location is often in high-risk areas, such as the scalp, ears or lips, or in areas that are commonly exposed to the sun (24). Diagnostic criteria for in-transit SCC have been proposed, owing to the difficulty in differentiating between diagnoses (25). Metastatic lesions that are distinct from prior surgical scars and situated between the main tumor and draining lymph nodes are included in the clinical criteria (26). Furthermore, the differential diagnosis encompasses local recurrence, perineural dissemination and other metastatic diseases. The following histological requirements should be fulfilled: The primary tumor must not have an epidermal origin, the primary tumor must not have a metastatic component and the metastatic tumor must be distinct from any prior surgical scars (27). A rare occurrence in cSCC is lymphovascular invasion, which refers to a tumor that involves or invades the lymphatics or arteries. Lymphovascular invasion is not considered in staging, despite the fact that it is a predictor of lymph node metastases, and, to the best of our knowledge, no research has thus far shown that it has independent prognostic value (28). Although immunosuppression, such as that seen after organ transplantation, is known to contribute to the development of aggressive SCC, immunocompetent individuals can also acquire in-transit SCC. The prognosis for these patients has been recorded in various ways, and the global disease-specific survival of combined organ transplant recipients and non-organ transplant recipients at 3 years has been reported to be 27-56% and the 5-year overall survival to be 13% (29).


PNI is the process of malignant invasion of nerves, and is an overlooked path of metastatic dissemination (30). Skin cancers of the head and neck region may penetrate the subarachnoid space of the cerebral cavity via this gap. PNI can be categorized into that discovered by chance during a medical investigation, also known as pathological PNI (pPNI); and that involving a specific nerve, also known as clinical PNI (cPNI) (31). A prior history of pPNI is not always present in patients with cPNI. The trigeminal (V) and facial (VII) cranial nerves are often affected by cPNI, typically proceeding from the skin to the brain in a retrograde manner. Aggressive disease behavior is linked to extratumoral disease, excessive nerve diameter and multifocal PNI. In contrast to BCC, cPNI is more aggressive when it occurs in cSCC (32). According to Jackson et al, in a study of 118 patients, 5-year local control rates for pPNI were reported to be 90%, whereas those for cPNI were only 57% (33). Risk factors for PNI in SCC are male sex, tumor size >2 cm, midfacial tumor site, recurring tumor, poorly defined histological subtypes and considerable subclinical expansion. These patients should be queried about any symptoms they may be experiencing, such as tingling, numbness, discomfort, paralysis or formication (34). Any tumor mass close to the main nerve trunk should be detected during the physical examination. Deficits in the trigeminal nerve distribution should be assessed via sensory testing (35). The Schirmer test, taste test and impedance audiometry can be used to determine whether the facial nerve is paralyzed. Notably, ptosis, ophthalmoplegia or visual abnormalities could indicate the involvement of cranial nerves II, III, IV or VI (36). Preoperative imaging investigations are crucial adjunctive tools in the initial assessment of high-risk patients with SCC, in addition to the evaluation of the signs and symptoms of PNI (37). Magnetic resonance imaging (MRI) or CT are the most commonly used methods for radiographic imaging of PNI (38). Based on the presence of nerve enhancement or enlargement, or the absence of the typical fat plane surrounding a nerve, MRI can detect the extent of macroscopic disease (39). Bone erosion caused by tumor invasion of the foramina connected to the cranial nerves can be visualized via CT scanning. Notably, a patient may have positive imaging scans without neurological signs of the illness. The importance of early diagnosis of PNI in SCC cannot be underestimated as appropriate and aggressive therapy must be initiated (40). In general, recommendations for postoperative radiotherapy are based on the mortality linked to PNI (41), as well as concerns about the accuracy of surgical margins (42). Owing to insufficient tumor removal, conventional excision alone may put patients with SCC and PNI at a significant risk for local recurrence (43); therefore, following surgery, radiotherapy is often advised as adjuvant therapy. Notably, to the best of our knowledge, no previous study has separated data into groups based on radiotherapy alone and radiotherapy combined with surgical resection.

Circulating tumor cells (CTCs)

CTCs, which are derived from the initial tumor (44), are shed during the lymphatic and/or vascular infiltration process into the bloodstream, causing the spread of cancer (45). These CTCs can be easily detected in peripheral blood, and are often used for the surveillance of breast, lung, colorectal and prostate cancer (46). These cells may exist alone or as microemboli (47). Tumor cells can spread to distant locations after entering the circulatory space, and CTCs make it possible to conduct ‘liquid biopsies’ and offer ‘real-time’ monitoring (48). CTC determination can aid in tracking the development or recurrence of the disease in real time, and identify patients for which treatment should be initiated or modified (49). Given that cSCC is the most prevalent type of nonmelanoma skin malignancy with a high risk of metastasis, being able to identify the few patients who develop metastases would have a significant impact on public health, especially in areas with notable sun exposure (50). The identification of CTCs as indicators of metastatic disease can also directly influence therapeutic practice via the early detection of recurrence and the development of specialized treatment procedures for high-risk patients (51). It could be hypothesized that using mesenchymal and novel biomarkers to broaden CTC markers in a positive selection model may enable higher levels of detection and enhance understanding of the metastatic process in cSCC.

4. Immunotherapy

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).

Table I

Trials considering novel therapies for head and neck cSCC.

Table I

Trials considering novel therapies for head and neck cSCC.

Trial registration numberMalignancyInterventionPrimary outcome(Refs.)
NCT04154943Stage II-IV cSCCIntravenous cemiplimab every 21 daysPathological complete response rate assessed by independent central pathology review(124)
NCT03916627Non-small cell lung cancer; hepato-cellular carcinoma; HNSCCCemiplimab; platinum doublet; fianlimabMajor treatment effect at time of surgery was the primary endpoint for the HNSCC cohort(125)
NCT03969004cSCCCemiplimab; placeboTo compare disease-free survival of patients with high-risk cSCC treated with adjuvant cemiplimab vs. those treated with placebo, after surgery and radiation therapy(126)
NCT03833167cSCC as the primary site of malignancyPembrolizumab (400 mg); placeboRecurrence-free survival as assessed by the investigator and confirmed by biopsy (time frame: up to ~60 months)(127)

[i] HNSCC, head and neck squamous cell carcinoma; cSCC, cutaneous squamous cell carcinoma.

5. Chemotherapy

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.

Table II

Chemotherapy drugs used in cutaneous squamous cell carcinoma.

Table II

Chemotherapy drugs used in cutaneous squamous cell carcinoma.

First author, yearDrug agentCategoryMethodOutcomesAdverse symptoms(Refs.)
Rades et al, 2023CisplatinPlatinum basedDNA crosslink88.5% response rateBone marrow suppression;kidney failure(128)
Rades et al, 2023CarboplatinPlatinum basedNon-specific cell cycle83% overall survival rateHypoxia and bronchospasm, and anaphylaxis(128)
Kurosaki et al, 2021CetuximabAntibody drugEGFR inhibitor49 months overall survivalInterstitial pneumonia; hypomagnesemia(129)
Chen et al, 2023Pembrolizumab and nivolumabAnti-PD-1 antibodyPD-1 receptor inhibitor7.7 months overall survivalDiabetes mellitus; colitis; interstitial pneumonia(130)

[i] EGFR, epidermal growth factor receptor.

6. Radiotherapy

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).

Table III

Adverse symptoms and overall survival rate from studies of patients with head and neck cutaneous squamous cell carcinoma undergoing fractionated radiotherapy.

Table III

Adverse symptoms and overall survival rate from studies of patients with head and neck cutaneous squamous cell carcinoma undergoing fractionated radiotherapy.

First author, yearNo. of patientsRadiation doseAdjuvant therapyAdverse symptomsOutcomes(Refs.)
Nottage et al, 201721EBRT, 70 GyYesThrombocytopenia, anemia, hearing loss, fibrosis, leukopenia1-year overall survival rate, 80.2%(131)
Cowey et al, 201982EBRTYesNoOverall survival rates: 1-year, 56.1%; 2-year, 30.2%; 3-year, 15.6%(132)
Lavaud et al, 20194Hypofractionated EBRT, 26 GyYesNoDisease-free survival, 14.4 months; overall survival, 15.6 months(133)
Fan et al, 2020166Hypofractionated EBRTYesDysphagia, trismus, dermatitis, mucositisRecurrence rate, 66%; 1-year overall survival rate, 25.3%(134)
Ogata et al, 2020130EBRTYesSkin ulcer, anemia, duodenal ulcer, heart failure, febrile neutropenia, erythema multiforme5-year overall survival rate, 29%(135)
De Felice et al, 202118 Ultra-hypofractionated EBRTNoNoOverall survival rates: 1-year, 66%; 2-year, 26.4%(136)
Voruganti et al, 202177SBRTNoDermatitis, mucositis, skin ulceration, fibrosisOverall survival rates: 1-year, 44%; 2-year, 26%(137)

[i] EBRT, external beam radiation therapy; SBRT, stereotactic body radiation therapy.

7. Future therapies

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).

8. Discussion

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.


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Funding: No funding was received.

Availability of data and materials

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Authors' contributions

DI wrote the original draft, and contributed to study conception and analysis of the literature. ALT and IF contributed to supervision, writing, conception, design, analysis of the literature, and reviewed and edited the manuscript. DV, AZ and MIS contributed to collection of the literature, study conception and manuscript editing. Data authentication is not applicable. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



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Iancu D, Fulga A, Vesa D, Zenovia A, Fulga I, Sarbu M and Tatu A: Metastatic patterns and treatment options for head and neck cutaneous squamous cell carcinoma (Review). Mol Clin Oncol 20: 40, 2024
Iancu, D., Fulga, A., Vesa, D., Zenovia, A., Fulga, I., Sarbu, M., & Tatu, A. (2024). Metastatic patterns and treatment options for head and neck cutaneous squamous cell carcinoma (Review). Molecular and Clinical Oncology, 20, 40.
Iancu, D., Fulga, A., Vesa, D., Zenovia, A., Fulga, I., Sarbu, M., Tatu, A."Metastatic patterns and treatment options for head and neck cutaneous squamous cell carcinoma (Review)". Molecular and Clinical Oncology 20.6 (2024): 40.
Iancu, D., Fulga, A., Vesa, D., Zenovia, A., Fulga, I., Sarbu, M., Tatu, A."Metastatic patterns and treatment options for head and neck cutaneous squamous cell carcinoma (Review)". Molecular and Clinical Oncology 20, no. 6 (2024): 40.