Head And Neck Cutaneous Squamous Cell Carcinoma Research Articles

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases

The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE). To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease. This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients. Curative intent surgery ± adjuvant radiotherapy. Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis. Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors. The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

Predictors of distant metastatic recurrence in head and neck cutaneous squamous cell carcinoma with lymph node metastases treated with curative intent: A multicenter study.

We aimed to identify predictors of distant metastatic recurrence (DMR) in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases treated with curative intent. Predictors of DMR were identified using Cox regression in a multicenter study of 1151 patients. The 5-year risk of DMR was 9.6%. On multivariate analysis, immunosuppression (HR 2.93; 95% CI: 1.70-5.05; p < 0.001), nodal size >6 cm [versus ≤3 cm (HR 2.77; 95% CI: 1.09-7.03; p = 0.032)], ≥5 nodal metastases [versus 1-2 (HR 2.79; 95% CI: 1.63-4.78; p < 0.001)], and bilateral disease (HR 3.11; 95% CI: 1.40-6.90; p = 0.005) predicted DMR. A DMR risk score was developed that stratified risk from 6.6% (no risk factors) to 100% (≥3 risk factors) (p < 0.001). The risk of DMR in nodal metastatic HNcSCC increases with immunosuppression, nodal size >6 cm, ≥5 nodal metastases, and bilateral disease. A simple DMR risk score estimated prior to treatment may be clinically useful.

Metastatic malignancies in the parotid gland: A retrospective study

The aim of this study was to compare treatment modalities, pathological and clinical characteristics, and outcomes in patients with metastasis in a parotid gland.The medical records of 34 patients who received treatment for metastasis in the parotid gland over a twenty-year period were evaluated. Patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) metastasis were retrospectively reclassified using the P/N and N1S3 staging system.Patients with neck metastasis showed a significantly poorer prognosis (P = 0.025). Univariate analysis also revealed that extent of parotidectomy and type of neck dissection did not influence recurrence free survival (RFS) and overall survival (OS). When comparing the usefulness of the P/N and S1N3 staging systems, a positive correlation was observed between the P stage and the N1S3 stage in both RFS and OS.The extent of parotidectomy and concomitant neck dissection is still under discussion. Total parotidectomy and modified radical neck dissection did not improve RFS and OS. N1S3 is a less complex classification and possesses a higher predictive value when compared to the P/N staging system.

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.

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.

Our 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. Patients 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. A 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 < 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. In 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.

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.

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.

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.

COMPARISON OF FEATURES AND OUTCOMES OF VERMILION LIP SCC WITH ORAL AND HEAD AND NECK CUTANEOUS SCC

<h3>Objectives</h3> Comparing features and outcomes of patients with skin, lip, and oral squamous cell carcinoma (SCC) and evaluating restaging lip cancer as skin cancer. <h3>Study Design</h3> All patients surgically treated at our center for vermilion lip SCC, oral SCC, and cutaneous head and neck (HN) SCC between January 2011 and December 2019 were retrospectively reviewed. <h3>Results</h3> 79, 125, and 620 cases were respectively included. Lip and oral SCC were similar regarding tumor diameter (<i>P</i> < .001), depth of invasion (<i>P</i> < .001), surgical margins (<i>P</i> = .01), T stage (<i>P</i> < .001), N stage (<i>P</i> < .001), AJCC stage (<i>P</i> < .001), perineural invasion (<i>P</i> < .001), and vascular invasion (<i>P</i> < .001). In total, 31 lip SCC cases were restaged applying cutaneous HN SCC staging system criteria, with a shift from stages I/II and T1/2 to stages III and T3, respectively. In Kaplan-Meier curves, there was a good distinction among staging curves for oral SCC and cutaneous SCC but not for lip SCC, in both staging models. <h3>Conclusions</h3> There are more similarities between lip SCC and cutaneous HN SCC than oral SCC, although both staging systems failed to distinguish categories in Kaplan-Meier curves.

Survival outcomes of perineural spread in head and neck cutaneous squamous cell carcinoma.

AimTo present an institution's experience and survival outcomes for patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) and perineural spread (PNS).MethodRetrospective study of patients with HNcSCC and PNS treated between January 2010 and August 2020 from the Sydney Head and Neck Cancer Institute database, Sydney, Australia; a high‐volume, tertiary, academic head and neck centre. Patient demographics, primary site, involved cranial nerves, treatment modality, loco‐regional failure and survival data were obtained.ResultsForty‐five patients were identified, of which 32 patients were male (71%). Mean age at diagnosis was 68.7 years (range 43–90). Median follow‐up was 16.1 months (range 1–107). The trigeminal nerve was most frequently involved (n = 30, 66.6%) followed by facial nerve (n = 13, 28.9%). Most patients underwent surgery followed by radiotherapy (n = 33, 73%) and eight received definitive radiotherapy. The median overall survival (OS) was 4.5 years (95% CI 3.71–5.38), median disease‐specific survival 5.1 years (95% CI 4.21–5.97) and median disease‐free survival (DFS) was 1.7 years (95% CI 1.11–2.22). The estimated 5‐year OS and DFS were 45% and 25%, respectively. Patients treated with surgery and adjuvant radiotherapy with a clear proximal nerve margin had favourable DFS (P = 0.035) and trended towards better OS (P = 0.134) compared with patients with an involved nerve margin. Patients treated surgically with involved proximal nerve margins had similar outcomes compared with patients with treated definitive radiotherapy (HR 0.80, 95% CI 0.29–2.22, P = 0.664).ConclusionThe likelihood of achieving a clear proximal nerve margin should be a strong consideration in the selection of appropriate patients for primary surgery

Recursive Partitioning to Determine Order of Significance of Regional Metastasis Characteristics in Head and Neck Cutaneous Squamous Cell Carcinoma.

The order of significance of clinicopathologic characteristics for the prognosis of patients with regional metastases from head and neck cutaneous squamous cell carcinoma (HNcSCC) is not well characterized. This study aimed to understand the impact of the known characteristics, including the presence of immunosuppression, number of deposits, largest deposit size, location and laterality of deposits, and presence of extranodal extension (ENE) on overall survival (OS) and disease-specific survival (DSS). A retrospective study of 366 patients treated with curative intent for HNcSCC with regional metastatic disease was undertaken using recursive partitioning analysis (RPA). Using RPA modeling, the study determined that number of metastatic deposits carried the highest impact for both OS and DSS, followed by largest deposit size. The presence of ENE and immunosuppression was less significant. The results from this study provide new evidence for identifying and stratifying high-risk patients with metastatic HNcSCC. This information will be valuable in determining future HNcSCC staging systems.

Locoregional Recurrence Trends in Head and Neck Cutaneous Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Predictors of locoregional recurrence in head and neck cutaneous squamous cell carcinoma (HNCSCC) are poorly understood. Two staging methods are used to stratify recurrence and survival risk and including the American Joint Committee on Cancer (AJCC, 8^th edition) and the Brigham Women's Hospital (BWH) systems. Our objective was to compare the predictive 2-year locoregional recurrence rates between these systems. <h3>Materials/Methods</h3> A single-institution, retrospective review from 2015-2020 was conducted of patients who underwent resection of locally advanced HNCSCC. Data collected included patient age, sex, recurrence status, tumor features (location, grade, diameter, depth of invasion, perineural invasion, lymphovascular invasion), cervical nodal disease, AJCC and BWH staging, adjuvant radiation, and 2-year follow-up. Two-sided comparisons were made between those with and without locoregional recurrence. Separate Kaplan-Meier and Cox proportional hazard models were generated comparing AJCC T3-T4 disease and BWH T2b-T3 disease and analyzed using log-rank test. Significance determined at p<0.05. <h3>Results</h3> A total of 132 patients were included and were overwhelmingly male (90.0%) with mean age 70.9 ± 11.0 years. Of these, 26 experienced locoregional recurrence within 2 years from resection (19.7%). Those with recurrence were more likely to present with recurrent disease (73.1% vs. 24.5%, p<0.001), have higher grade (p=0.048), larger tumors (>2.0 cm, 79.2% vs. 43.5%, p=0.003) in high-risk locations (88.5% vs 55.7%, p=0.002) and receive adjuvant radiation (53.8% vs. 27.4%, p=0.018). No statistical difference was identified between age, sex, immunosuppression, lymphovascular or perineural invasion, or nodal disease. Kaplan-Meier curves comparing AJCC T3-T4 and BHW T3b-T3 disease demonstrated significant (p<0.001) and similar 2-year locoregional recurrence at 36.5% and 41.2%, respectively. Separate, multivariate Cox proportional hazard modeling of 2-year locoregional recurrence adjusting for recurrent disease and high-risk tumor location demonstrated hazard ratios (95% CI) of 2.73 (1.12-6.63) for AJCC T3-T4 disease and 5.02 (1.37-18.44) for BHW T2b-T3. <h3>Conclusion</h3> The BWH and AJCC staging systems have comparable 2-year locoregional recurrence rates after resection of HNCSCC. Controlled, prospective trials are required to further comparison.

Redefining Perineural Invasion in Head and Neck Cutaneous Squamous Cell Carcinoma.

Perineural invasion (PNI) negatively affects disease-specific survival in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC). We aim to analyze the prognostic implications of PNI-related features. Retrospective cohort study. Academic tertiary care hospital. Retrospective chart review was performed on 104 patients diagnosed with HNcSCC between January 2011 and October 2019 who underwent resection, parotidectomy, and neck dissection with more than 1 year of follow-up. PNI was classified as incidental (identified on histopathology alone) or clinical (present on radiography and/or physical exam). Primary outcome measures were overall survival and disease-free survival (DFS). Kaplan-Meier analysis, logistic regression, and Cox regression were performed. The overall 5-year DFS was 57.9%. Sixty-one patients had PNI. On histopathology, 28 lesions showed complete nerve encirclement, 10 involved >5 nerves, and 12 involved named nerves. Patients with facial weakness (P = .026) and positive margins (P = .0029) had a higher likelihood of histopathologic PNI, and positive margins retained significance on multivariable analysis (P = .0079). Worse DFS was seen in patients with PNI (P = .004), advanced tumor stage (P = .049), positive margins (P = .014), and >5 nerves involved (P = .0061). Furthermore, histopathologic PNI was a predictor of DFS (hazard ratio [HR], 3.07; 95% CI, 0.33-1.38; P = .0061) overall and in the clinical PNI cohort (HR, 3.43; 95% CI, 1.65-7.10; P = .00091). DFS was significantly worse in patients with PNI, facial nerve weakness, advanced T stage, positive margins, and multiple nerve involvement. Further characterization of PNI features may help improve prognostic predictions and identify patients who may benefit from more aggressive treatment.

Lymphatic drainage map of the head and neck skin squamous cell carcinoma detected by sentinel lymph node biopsy.

Squamous cell carcinoma of the skin often affects the scalp and neck region and has a potential for complex lymphatic metastases. The aim of this study was to examine the pattern of lymphatic drainage that would enable better insight and prediction of lymphatic metastasis of head and neck squamous cell carcinoma (HNSCC) in relation to the anatomical localization of the primary process. A prospective analysis included 64 patients who underwent sentinel lymph node (SLN) biopsy. The biopsy was performed in patients with high-risk cutaneous head and neck squamous cell carcinoma between 2006 and 2010. SLNs in tumors of the forehead, temporal region, lateral cheek, and auricle were found in the cervical region at level II and parotid lymph nodes (p<0.001). In tumors of the nose, periorbital region, and postauricular tumors, SLNs were found in parotid lymph nodes (p<0.001), in tumors of the medial cheek in level I cervical lymph nodes and parotid lymph nodes (p=0.003). In tumors of the neck, SLNs were detected in the cervical region at level IV, whereas in tumors of the posterior scalp they were found in the occipital region (p<0.001). The results of SLN biopsy in high-risk cutaneous HNSCCs show the regularity of metastasis based on which a lymphatic drainage map can be constructed and thus potential metastatic sites depending on the primary tumor localization predicted.

High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Clinical Review.

Given the rapidly evolving nature of the field, the current state of "high-risk" head and neck cutaneous squamous cell carcinoma (HNcSCC) is poorly characterized. Narrative review of the epidemiology, diagnosis, workup, risk stratification, staging and treatment of high-risk HNcSCC. Clinical and pathologic risk factors for adverse HNcSCC outcomes are nuanced (e.g., immunosuppression and perineural invasion). Frequent changes in adverse prognosticators have outpaced population-based registries and the variables they track, restricting our understanding of the epidemiology of HNcSCC and inhibiting control of the disease. Current heterogeneous staging and risk stratification systems are largely derived from institutional data, compromising their external validity. In the absence of staging system consensus, tumor designations such as "high risk" and "advanced" are variably used and insufficiently precise to guide management. Evidence guiding treatment of high-risk HNcSCC with curative intent is also suboptimal. For patients with incurable disease, an array of trials are evaluating the impact of immunotherapy, targeted biologic therapy, and other novel agents. Population-based registries that broadly track updated, nuanced, adverse clinicopathologic risk factors, and outcomes are needed to guide development of improved staging systems. Design and development of randomized controlled trials (RCTs) in advanced-stage HNcSCC populations are needed to evaluate (1) observation, sentinel lymph node biopsy, or elective neck dissection for management of the cN0 neck, (2) indications for surgery plus adjuvant radiation versus adjuvant chemoradiation, and (3) the role of immunotherapy in treatment with curative intent. Considering these knowledge gaps, the authors explore a potential high-risk HNcSCC treatment framework.

Gene expression profiling of perineural invasion in head and neck cutaneous squamous cell carcinoma

Perineural invasion (PNI) is frequently associated with aggressive clinical behaviour in head and neck cutaneous squamous cell carcinoma (HNcSCC) leading to local recurrence and treatment failure. This study evaluates the gene expression profiles of HNcSCC with PNI using a differential expression analysis approach and constructs a tailored gene panel for sensitivity and specificity analysis. 45 cases of HNcSCC were stratified into three groups (Extensive, Focal and Non PNI) based on predefined clinicopathological criteria. Here we show HNcSCC with extensive PNI demonstrates significant up- and down-regulation of 144 genes associated with extracellular matrix interactions, epithelial to mesenchymal transition, cell adhesion, cellular motility, angiogenesis, and cellular differentiation. Gene expression of focal and non PNI cohorts were indistinguishable and were combined for further analyses. There is clinicopathological correlation between gene expression analysis findings and disease behaviour and a tailored panel of 10 genes was able to identify extensive PNI with 96% sensitivity and 95% specificity.

The significance of regional metastasis location in head and neck cutaneous squamous cell carcinoma.

Regional metastasis of head and neck cutaneous squamous cell carcinoma (HNcSCC) can be seen in either parotid and/or cervical lymph nodes. The aim of this study was to assess whether there was a difference in prognosis between parotid and cervical nodal metastases. Patients with regional metastasis from HNcSCC were identified from an institutional database. Disease-specific (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method and Cox proportional hazards models. Five hundred and thirty-five patients were identified with median follow-up of 26.4months (3-255 months). Two hundred and thirty-five patients had parotid metastasis, 96 patients had neck metastasis, and 204 patients had both. On multivariable analysis, any regional metastasis to the neck when compared to parotid alone conferred worse DSS (HR 1.8, p=0.007) and OS (HR 1.3, p=0.024). Regional metastasis of HNcSCC to the neck confers worse outcomes compared to metastasis to the parotid alone.

Inclusion of extranodal extension in the lymph node classification of cutaneous squamous cell carcinoma of the head and neck.

The prognostic performance of the recently updated American Joint Committee on Cancer lymph node classification of cutaneous head and neck squamous cell carcinoma (HNSCC) has not been validated. The objective of this study was to assess the prognostic role of extranodal extension (ENE) in cutaneous HNSCC. This was a retrospective analysis of 1258 patients with cutaneous HNSCC who underwent surgery with or without adjuvant therapy between 1995 and 2019 at The University of Texas MD Anderson Cancer Center. The primary outcome was disease-specific survival (DSS). Local, regional, and distant metastases-free survival were secondary outcomes. Recursive partitioning analysis (RPA) and a Cox proportional hazards regression model were used to assess the fitness of staging models. No significant differences in 5-year DSS were observed between patients with pathologic lymph node-negative (pN0) disease (67.4%) and those with pN-positive/ENE-negative disease (68.2%; hazard ratio, 1.02; 95% CI, 0.61-1.79) or between patients with pN-positive/ENE-negative disease and those with pN-positive/ENE-positive disease (52.7%; hazard ratio, 0.57; 95% CI, 0.31-1.01). The RPA-derived model achieved better stratification between high-risk patients (category III, ENE-positive with >2 positive lymph nodes) and low-risk patients (category I, pN0; category II, ENE-positive/pN1 and ENE-negative with >2 positive lymph nodes). The performance of the RPA-derived model was better than that of the pathologic TNM classification (Akaike information criterion score, 1167 compared with 1176; Bayesian information criterion score, 1175 compared with 1195). The number of metastatic lymph nodes and the presence of ENE are independent prognostic factors for DSS in cutaneous HNSCC, and incorporation of these factors in staging systems improves the performance of the American Joint Committee on Cancer lymph node classification.