Neck Cutaneous Squamous Cell Carcinoma Research Articles

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

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.

Sentinel lymph node biopsy versus observation in high risk cutaneous squamous cell carcinoma of head and neck: a propensity score matching analysis.

Sentinel lymph node biopsy (SLNB) has gained considerable attention in the management of head and neck cutaneous squamous cell carcinoma (HNcSCC). The aim of this study was to compare the oncologic outcomes between observation and SLNB in cN0 high-risk HNcSCC patients. We retrospectively enrolled patients from the SEER database and evaluated the impact of observation versus SLNB on disease-specific survival (DSS) and overall survival (OS) using a Propensity Score Matching (PSM) analysis. A total of 9804 patients were included, with 1169 cases treated by SLNB. Successful retrieval of the sentinel lymph node was achieved in 1130 procedures. After PSM and subsequent multivariate analysis, SLNB was found to be an independent predictor for improved DSS, with a hazard ratio of 0.70 (95% confidence interval: 0.56-0.86). In patients presenting with two or three high-risk factors, SLNB was associated with better DSS (p = 0.021 and p = 0.044), but similar OS (p = 0.506 and p = 0.801) when compared to observation. However, in patients exhibiting four high-risk factors, SLNB demonstrated significantly improved DSS (p = 0.040) and OS (p = 0.028) compared to observation. Our findings suggest that SLNB is a highly feasible technique in HNcSCC and provides significant survival benefits. It is strongly recommended in patients with two or more high-risk factors, as it can help guide treatment decisions and improve patient outcomes.

Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

Tumour Recurrence, Depth of Invasion, and Temple Location as Independent Prognostic Parameters of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinomas.

The excellent survival rate of cutaneous squamous cell carcinoma (cSCC) exceeding 90% is reduced by the presence of nodal metastases by over 50%. We analysed various risk parameters of cSCC to predict the incidence of nodal metastases. A total of 118 patients with the head cSCC were included in a single-institution retrospective study covering the period from 2008 to 2020. Tumour recurrence, temple location, and tumour infiltration depth were found to be independent predictors of nodal metastases (increasing the probability of metastases by 8.0, 8.1, and 4.3 times, respectively). Furthermore, univariate analysis shows that the tumour size and T stage are significant factors increasing the risk of metastases. Several independent risk factors for the development of metastases in the head cSCC have been confirmed. These findings might help identify at-risk patients who require additional attention for adequate radical treatment and close follow-up. In contrast, elective treatment of lymph nodes is not recommended due to the low incidence of regional metastases.

129 Regional Experience of Cemiplimab, in Locally advanced and stage IV Head and Neck Cutaneous Squamous Cell Carcinomas

129 Regional Experience of Cemiplimab, in Locally advanced and stage IV Head and Neck Cutaneous Squamous Cell Carcinomas

Neck management in metastatic cutaneous squamous cell carcinoma of the head and neck.

Optimal neck management remains unclear in head and neck cutaneous squamous cell carcinoma (HNcSCC) with parotid metastasis. Our goal was to compare the impact of different cervical treatments on HNcSCC with parotid metastasis. Patients were retrospectively included. The primary outcome variables were regional control (RC) and disease-specific survival (DSS). The impacts of observation, elective neck irradiation (ENI), and elective neck dissection (END) were analyzed using the Cox model and presented as hazard ratios (HRs) and 95% confidence intervals (CIs). In total, 268 patients were enrolled. In the Cox model for RC, compared with ENI, observation was associated with a significantly higher risk of regional recurrence (p = 0.001, HR = 2.50, 95%CI = 1.45-4.30). However, END showed a comparable influence on regional recurrence (p = 0.246, HR = 0.70, 95%CI = 0.38-1.28). In the Cox model for DSS, END demonstrated a similar HR of 0.62 (95%CI = 0.30-1.26) compared to ENI (p = 0.184). However, patients who underwent observation were associated with an additional nearly twofold risk of cancer-related mortality (HR = 2.85, 95%CI = 1.55-5.23). Subgroup analysis showed that ENI predicted comparable RC (p = 0.389) and DSS (p = 0.346) in patients with one or two metastatic parotid lymph nodes, but worse RC (p = 0.007) and DSS (p = 0.024) in patients with more than three positive lymph nodes. In HNcSCC with parotid metastasis, elective treatment of neck lymph nodes with END or ENI should always be performed.

Neck management in cutaneous squamous cell carcinoma with parotid metastasis

AbstractObjectiveOur objective is to assess the oncologic outcomes of observation, elective neck dissection (END), and elective neck irradiation (ENI) in the neck management of head and neck cutaneous squamous cell carcinoma (HNcSCC) with parotid metastasis (P+) and to evaluate the quality of life (QoL) of patients who received END or ENI.MethodsPatients with P+ HNcSCC were retrospectively enrolled. The impact of observation, END, and ENI on regional control (RC) and overall survival (OS) was analyzed using Cox proportional hazards model with presentation via hazard ratio (HR) with a 95% confidence interval (CI). QoL was evaluated using the University of Washington Quality of Life questionnaire.ResultsA total of 134 patients were included in our analysis. In the Cox model for RC, both END and ENI had decreased HRs of 0.27 (95% CI: 0.15–0.69) and 0.34 (95% CI: 0.18–0.86), respectively, in comparison with observation. In the Cox model for OS, both END (p = 0.001, HR: 0.22, 95% CI: 0.10–0.72) and ENI (p = 0.006, HR: 0.30, 95% CI: 0.17–0.83) were superior to observation. In patients with three or more positive parotid lymph nodes, END resulted in significantly better RC (p &lt; 0.001) and OS (p = 0.001) compared with ENI. The two groups were found to be comparable in all 12 domains of the University of Washington Quality of Life questionnaire.ConclusionIn the neck management of P+ HNcSCC, observation is not recommended. END is the preferred option, but ENI is an alternative method without compromise to survival or QoL, except in cases with three or more metastatic parotid lymph nodes.

Performance of Staging Systems for Non-Head and Neck Cutaneous Squamous Cell Carcinoma.

The performance of staging systems in non-head and neck cutaneous squamous cell carcinomas has not been well established. To evaluate the performance of the American Joint Committee on Cancer 8th Edition and Brigham and Women's Hospital staging systems in non-head and neck squamous cell carcinomas. Eligible tumors were identified and staged from an existing retrospective database. Cumulative incidence function curves of any poor outcome were generated. Distinctiveness, sensitivity, specificity, positive and negative predictive value, and concordance index were calculated. 1,042 primary tumors were included, with 38 resulting in any poor outcome and 16 in any major poor outcome. High-stage tumors represented 2.2% and 3.5% of tumors; these accounted for 10/38 of the poor outcomes (26.3%) and 8/16 of the major poor outcomes (50%). High-stage tumors predicted major poor outcomes with a sensitivity of 0.5 and specificity of 0.99 for the Brigham and Women's Hospital system, and a sensitivity of 0.5 and specificity of 0.97 for the American Joint Committee on Cancer 8th edition system. The concordance index for both was 0.74. Current staging systems can be used to predict poor outcomes in cutaneous squamous cell carcinomas off the head and neck.

Persisting facial nerve palsy or trigeminal neuralgia - red flags for perineural spread of head and neck cutaneous squamous cell carcinoma (HNcSCC).

Perineural spread (PNS) of head and neck cutaneous squamous cell carcinoma (HNcSCC) is a unique diagnostic challenge, presenting with insidious trigeminal (CN V) or facial nerve (CN VII) neuropathies without clinically discernible primary masses. These patients are often sub-optimally investigated and misdiagnosed as Bell's palsy or trigeminal neuralgia. This case series highlights the red flags in history and pitfalls that lead to delays to diagnosis and treatment. A retrospective case series of 19 consecutive patients with complete clinical histories with HNcSCC PNS without an obvious cutaneous primary lesion at time of presentation to a quaternary head and neck centre in Australia were identified and included for analysis. Fifteen had CN VII PNS, 17 had CN V PNS, and 13 had both. The overall median symptom-to-diagnosis time was 12-months (IQR-15 months). Eight patients had CN VII PNS and described progressive segmental facial nerve palsy with a median symptom-to-diagnosis time of 9-months (IQR-11.75 months). Eleven patients had primary CN V PNS and described well localized parathesia, formication or neuralgia with a median symptom-to-diagnosis time of 19-months (IQR 27.5 months). PNS is often mistaken for benign cranial nerve dysfunction with delays in diagnosis worsening prognosis. Red flags such as progressive CN VII palsy or persistent CN V paraesthesia, numbness, formication or pain, particularly in the presence of immuno-compromise and/or a history of facial actinopathy should raise suspicion for PNS. Gadolinium-enhanced MR Neurography should be obtained expediently in patients with persistent/progressive CN V/CN VII palsies in patients with red flags, with low threshold for referral to a Head and Neck Surgeon.

Comprehensive profiling identifies tumour and immune-microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinomas (CSCC) are the second most diagnosed skin cancer worldwide, however, little is known about the pathobiological factors contributing to the diverse clinical outcomes observed. To comprehensively profile CSCC and identify pathological processes contributing to the disparities in clinical behaviour observed. We characterised the genomic, transcriptomic and immunohistochemical profiles of 206 CSCC tumours, including 37 CSCC from immunocompromised patients. CSCC from immunocompromised patients are characterised by the lack of B cells in the peri-tumoural stromal compared to immunocompetent patients. Further, the abundance of a memory B cell-like population in the peritumoural stroma is associated with better prognosis in all patients (immunocompetent and immunocompromised) as well as only immunocompetent patients. No differences in genetic variants, tumour mutational burden or mutational signatures were observed between CSCC from immunocompetent and immunocompromised patients. Thus, differences in survival between CSCC from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but rather associated with differential host immune response. Non-head and neck primary site CSCC have lower tumour mutational burden and exhibit upregulation of the epithelial-mesenchymal transition programme compared to head and neck CSCC. Both factors are implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. In summary, we identify tumour and host immune factors that contribute to the disparate clinical behaviour of CSCC with broad translational application including prognostication, treatment prediction to current therapies and identifying novel anti-cancer therapy approaches in CSCC.

Radiation therapy for low- and high-risk perineural invasion in head and neck cutaneous squamous cell carcinoma: Clinical outcomes and patterns of failure.

Perineural invasion (PNI) in head and neck squamous cell carcinoma (HNSCC) portends poor prognosis. Extent of treatment of nerve pathways with varying degrees of PNI and patterns of failure following elective neural radiotherapy (RT) remain unclear. Retrospective review of HNSCC patients with high-risk (clinical/gross, large-nerve, extensive) or low-risk (microscopic/focal) PNI who underwent curative-intent treatment from 2010 to 2021. Forty-four patients (mean follow-up 22 months; 59% high-risk, 41% low-risk PNI) were included. Recurrence following definitive treatment occurred in 31% high-risk and 17% low-risk PNI patients. Among high-risk patients, 69% underwent surgery with post-operative RT and 46% underwent elective neural RT. Local control (83% low-risk vs. 75% high-risk), disease-free, and overall survival did not differ between groups. High local control rates were achieved in high-risk PNI patients treated with adjuvant or primary RT, including treatment of both involved and uninvolved, communicating cranial nerves, with few failures in electively treated regions.

Comparative Performance of Four Staging Classifications to Select «High-Risk» Head and Neck Cutaneous Squamous Cell Carcinomas.

Many classifications exist to select patients with "high-risk" head and neck cutaneous squamous cell carcinoma (HNCSCC). To compare the performance of the Brigham and Women's Hospital (BWH) classification with the performance of the American Joint Committee on Cancer 8th Edition (AJCC8), the Union for International Cancer Control 8th Edition (UICC8), and the National Comprehensive Cancer Network (NCCN) classifications. In this single-center retrospective study, HNCSCC resected in a tertiary care center were classified as "low-risk" or "high-risk" tumors according to the four classifications. Rates of local recurrence (LR), lymph node recurrence (NR), and disease-specific death (DSD) were collected. The performance of each classification was then calculated in terms of homogeneity, monotonicity, and discrimination and compared. Two hundred and seventeen HNCSCC from 160 patients, with a mean age of 80 years, were included. For predicting the risk of any poor outcome and risk of NR, the BWH classification had the best specificity and positive predictive value. However, its concordance index was not significantly higher than that of the AJCC8 and UICC8 classifications. The NCCN classification was the least discriminant. This study suggests that the BWH classification is the most appropriate for predicting the risk of poor outcomes in patients with HNCSCC when compared with the NCCN, UICC8, and AJCC8 classifications.

Comparing Genomic Landscapes of Oral and Cutaneous Squamous Cell Carcinoma of the Head and Neck: Quest for Novel Diagnostic Markers

Squamous cell carcinoma is the most common head and neck malignancy arising from the oral mucosa and the skin. The histologic and immunohistochemical features of oral squamous cell carcinoma (OSCC) and head and neck cutaneous squamous cell carcinoma (HNcSCC) are similar, making it difficult to identify the primary site in cases of metastases. With the advent of immunotherapy, reliable distinction of OSCC and HNcSCC at metastatic sites has important treatment and prognostic implications. Here, we investigate and compare the genomic landscape of OSCC and HNcSCC to identify diagnostically useful biomarkers. Whole-genome sequencing data from 57 OSCC and 41 HNcSCC patients were obtained for tumor and matched normal samples. Tumor mutation burden (TMB), Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, frequent chromosomal alterations, somatic single nucleotide, and copy number variations were analyzed. The median TMB of 3.75 in primary OSCC was significantly lower (P < .001) than that of 147.51 mutations/Mb in primary HNcSCC. The COSMIC mutation signatures were significantly different (P < .001) between OSCC and HNcSCC. OSCC showed COSMIC single-base substitution (SBS) mutation signature 1 and AID/APOBEC activity–associated signature 2 and/or 13. All except 1 HNcSCC from hair-bearing scalp showed UV damage–associated COSMIC SBS mutation signature 7. Both OSCC and HNcSCC demonstrated a predominance of tumor suppressor gene mutations, predominantly TP53. The most frequently mutated oncogenes were PIK3CA and MUC4 in OSCC and HNcSCC, respectively. The metastases of OSCC and HNcSCC demonstrated TMB and COSMIC SBS mutation signatures similar to their primary counterparts. The combination of high TMB and UV signature in a metastatic keratinizing squamous cell carcinoma suggests HNcSCC as the primary site and may also facilitate decisions regarding immunotherapy. HNcSCC and OSCC show distinct genomic profiles despite histologic and immunohistochemical similarities. Their genomic characteristics may underlie differences in behavior and guide treatment decisions in recurrent and metastatic settings.

Density of mast-cells and Microvessels Density in head and neck cutaneous Squamous Cell Carcinoma

Background and Aim: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. Mast cells may play a role in tumor progression and metastasis by increasing angiogenesis. The aim of this study was to investigate the role of mast cells by increasing angiogenesis in invasion of head and neck cutaneous squamous cell carcinoma.

DANGER: what clinicians need to know about aggressive head and neck cutaneous squamous cell carcinoma.

DANGER: what clinicians need to know about aggressive head and neck cutaneous squamous cell carcinoma.

Sex Disparity for Patients with Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Systematic Review.

The incidence of head and neck cutaneous squamous cell carcinoma (HNcSCC) is unevenly distributed between men and women. At present, the mechanism behind this disparity remains elusive. This study conducted a systematic review and meta-analysis of proportions to investigate the disparity between sexes for patients with HNcSCC. PubMed, Scopus, EMBASE, MEDLINE, Emcare and CINAHL were searched in November 2021 and June 2022 (N > 50, English, human), and studies which examined the association between sex and HNcSCC were included. Analysis was conducted using RStudio with data and forest plots displaying males as a proportion of total patients with HNcSCC. Two independent researchers performed study selection, data extraction, data analysis and risk of bias. Eighty-two studies (1948 to 2018) comprising approximately 186,000 participants (67% male, 33% female) from 29 countries were included. Significantly more males had HNcSCC overall (71%; CI: 67−74). Males were also significantly more affected by cSCC of the ear (92%; CI: 89−94), lip (74%; CI: 66−81), and eyelid (56%; CI: 51−62). This study found HNcSCC disproportionately affected males overall and across all subtypes. Improving our understanding of sex-specific mechanisms in HNcSCC will better inform our preventive, therapeutic and prognostic practices.

Proliferating Pilar Tumors Are Characterized by Recurrent 15q, 6q, and 6p22.2 Alterations.

Proliferating pilar tumors (PPTs) are rare neoplasms of external root sheath derivation, which most commonly occur on the scalp of elderly women. Although typically showing classic histologic features such as trichilemmal type keratinization, a lobular architecture and peripheral palisading, squamous cell carcinoma (SCC) remains a common diagnostic pitfall. Therefore, we sought to explore the molecular pathogenesis of PPTs and compare it with that of cutaneous squamous cell carcinoma (cSCC). Herein, we describe the use of a next-generation DNA sequencing platform to provide the most comprehensive molecular genetic analysis to date of a cohort of 5 PPTs and compare them to 5 head and neck cutaneous SCCs. Recurrent broad arm-level gains of 15q and concurrent single-copy losses of 6q and 6p22.2 were observed in 4 of 5 (80%) PPT cases. Other recurrent mutations or alterations of significance were not found in PPTs. Notably, these chromosomal changes were not identified in any of the 5 cutaneous SCCs, which instead showed recurrent alterations in the known SCC driver genes TP53 , CDKN2A , and NOTCH1 . Here, we show for the first time that PPTs are molecularly distinct from cutaneous SCC and provide evidence that recurrent alterations in chromosome 15 and chromosome 6 are central to the pathogenesis of PPTs.

235P Evaluation of a prognostic model for head and neck cutaneous squamous cell carcinoma using a cumulative number of risk factors

Cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous malignant tumor, occurring frequently in the head and neck. The latest National Comprehensive Cancer Network (NCCN) Guidelines classify cSCC into low-, high-, and very-high-risk groups using multiple risk factors. There were no detailed and accurate prognostic models for the newly established “very-high-risk” group. We identified the following four important risk factors for local relapse, nodal relapse, and SCC-related death in a previous study: recurrent tumor, high-risk histologic features, >6-mm tumor thickness or invasion beyond the subcutaneous fat layer, and lymphatic or vascular involvement.

Recent Advances in Immunotherapy for Patients with Head and Neck Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is the second most common non-melanoma skin cancer. A majority of patients present with localized disease, but some can present with locally advanced or metastatic disease. Most of these advanced cases occur in the anatomical head and neck region and are associated with more aggressive disease, necessitating prompt and effective treatment. Prior to the emergence of immunotherapy, systemic treatment options were limited to platinum-based chemotherapy and salvaged with targeted epidermal growth factor therapy. These therapies were associated with poor efficacy and increased toxicity in an often frail, older population. Immunotherapy has dramatically improved outcomes in this patient population due to its favorable side effect profile, durable treatment response, and improved overall outcomes. In this review, an overview of the recent advances of immunotherapy in the management of CSCC in the anatomical head and neck region is provided, with a focus on advanced presentations.

Evolution of Head and Neck Cutaneous Squamous Cell Carcinoma Nodal Staging-An Australian Perspective.

Simple SummaryAustralia has the highest incidence of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) in the world. Although the majority of HNcSCCs are cured by simple surgical excision, those that spread to lymph nodes require aggressive and debilitating surgery in conjunction with radiation therapy, with a significant risk of treatment failure and subsequent loss of life. Cancer staging is critical to guide prognosis, treatment (to maximise disease control and minimise morbidity), and for research. Australian institutions have been at the forefront of prognostication for HNcSCC with lymph node spread. Despite this, the search for a well performing staging system is ongoing. This review chronologically explores and summarises the Australian contribution to date and highlights the ongoing challenges.Cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is one of the commonest malignancies. When patients present with regional metastatic disease, treatment escalation results in considerable morbidity and survival is markedly reduced. Owing to the high incidence, Australian institutions have been at the forefront of advocating for reliable, accurate, and clinically useful staging systems that recognise the distinct biological characteristics of HNcSCC. As a result, an extensive body of literature has been produced over the past two decades, which has defined critical prognostic factors, critiqued existing staging systems, and proposed alternative staging models. Notwithstanding, a suitable staging system has proved elusive. The goal of cancer staging is to group patients according to cancer characteristics for which survival differs between groups (distinctiveness), consistently decreases with increasing stage (monotonicity), and is similar within a group (homogeneity). Despite implementing major changes based on published data, the latest edition of the American Joint Committee on Cancer (AJCC) staging manual fails to satisfy these fundamental requirements. This review chronologically explores and summarises the Australian contribution to prognostication and nodal staging of HNcSCC and highlights the ongoing challenges.