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

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.

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

BACKGROUND: 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). METHODS: A retrospective study of 366 patients treated with curative intent for HNcSCC with regional metastatic disease was undertaken using recursive partitioning analysis (RPA). RESULTS: 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. CONCLUSIONS: 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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: Five hundred and thirty-five patients were identified with median follow-up of 26.4 months (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). CONCLUSION: Regional metastasis of HNcSCC to the neck confers worse outcomes compared to metastasis to the parotid alone.

A critical analysis of the 8th edition TNM staging for head and neck cutaneous squamous cell carcinoma with lymph node metastases and comparison to N1S3 stage and ITEM risk score: A multicenter study.

BACKGROUND AND OBJECTIVES: We performed a critical analysis of the 8th edition American Joint Committee on Cancer (AJCC) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases and compared the performance to the N1S3 and ITEM systems. METHODS: Multicenter study of 990 patients with metastatic HNcSCC treated with curative intent. The end points of interest were disease-specific (DSS) and overall survival (OS). Model fit was evaluated using Harrell's Concordance Index (C-index), proportion of variation explained (PVE), Akaike information criterion, and Bayesian information criterion. RESULTS: N1S3 and ITEM demonstrated good distribution into risk categories in contrast to the AJCC system, which classified the majority (90.6%) of patients as N2-3 and Stage IV due to the high rate of extranodal extension. The N2c and N3a categories appeared redundant. There was considerable discordance between systems in risk allocation on an individual patient basis. N1S3 was the best performed (DSS: C-index 0.62, PVE 10.9%; OS: C-index 0.59, PVE 4.5%), albeit with relatively poor predictive value. CONCLUSIONS: The AJCC N category and tumor node metastasis stage have poor patient distribution and predictive performance in HNcSCC. The AJCC stage, N1S3, and ITEM score all provide limited prognostic information based on objective measures highlighting the need to develop a staging system specific to HNcSCC.

Soft Tissue Metastases in Head and Neck Cutaneous Squamous Cell Carcinoma.

OBJECTIVE: Soft tissue metastases (STM) in head and neck cutaneous squamous cell carcinoma (HNcSCC) are non-nodal based metastases to the parotid and cervical soft tissues of the head and neck. This is a unique subgroup of regional metastases amongst patients with cSCC and have been shown to be associated with poor prognosis. Detailed studies of this subgroup are lacking in the literature. A retrospective cohort analysis was performed to characterize the prognostic significance of STM in HNcSCC based on individual clinicopathological features. METHODS: Patients with HNcSCC with STM were identified from the Sydney Head and Neck Cancer Institute database. Clinicopathological characteristics were extracted from the histopathological reports. Recurrence and follow-up data were analyzed to determine disease-free and overall survival using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: After excluding all patients with lymph node metastasis with no STM, there were 200 patients identified (161 parotid, 32 cervical, and seven with concurrent parotid and cervical STM) with a 5-year overall survival of 36%. In univariable analysis, age of patients, size of the deposits, location of the deposits, and patients that were not offered adjuvant radiotherapy have worse overall survival. However, on multivariable analysis, age and the number of STM deposits were independent factors that predict for worse survival. CONCLUSION: The presence of STM in patients with HNcSCC is associated with poor prognosis. Increasing number of STM deposits, as well as involved margin of the regional excision, negatively impacted on the overall prognosis. LEVEL OF EVIDENCE: Level III - retrospective cohort study. Laryngoscope, 131:E1209-E1213, 2021.

Prognostic value of the 8th edition American Joint Commission Cancer nodal staging system for patients with head and neck cutaneous squamous cell carcinoma: A multi-institutional study.

BACKGROUND: The 8th edition American Joint Committee on Cancer staging manual (AJCC8) introduced a separate staging system for head and neck cutaneous squamous cell carcinoma (HNcSCC) which parallels mucosal SCC and incorporates extranodal extension (ENE). This study aims to evaluate its prognostic utility. METHODS: Univariate analysis of 1146 patients with metastatic HNcSCC from four Australian cancer centers was performed according to both AJCC 7th (AJCC7) and the 8th editions. RESULTS: AJCC8 increased classification of 924 (80.6%) patients to either pN2a or pN3b and 341 patients (29.8%) from stage III to IV compared to AJCC7. The disease-specific survival (DSS) was not significantly different between pN1, pN2 or pN3a categories per AJCC8. Estimates of model performance for the AJCC8 pN staging revealed modest predictive capacity (Harrell's C of 0.62 for DSS). CONCLUSIONS: The risk stratification according to pN classification of AJCC8 staging system performed poorly as a prognostic indicator.

Nodal metastasis size predicts disease-free survival in cutaneous head and neck squamous cell carcinoma involving the parotid but not cervical nodes.

BACKGROUND: The 8th edition American Joint Committee on Cancer nodal (N) staging of cutaneous squamous cell carcinoma of the head and neck (cSCCHN) is largely based on lymph node metastasis size, despite conflicting data in the literature. This study aimed to investigate the prognostic significance of largest node size in cSCCHN. METHODS: Retrospective analysis of 94 patients undergoing curative-intent treatment for nodal cSCCHN with surgery ± radiotherapy at Liverpool Hospital, Sydney, Australia was conducted. Survival outcomes were assessed using multivariate Cox regression. The primary end point was disease-free survival (DFS). Objective measures of model performance were used in exploratory analyses to identify optimal size thresholds for predicting survival. RESULTS: Nodal metastasis size significantly predicted DFS on multivariate analysis (hazard ratio 1.24; 95% confidence interval 1.06-1.46; P = 0.008). This prognostic impact occurred predominantly in parotid metastases (hazard ratio 1.27; 95% confidence interval 1.07-1.51; P = 0.006); each 1 cm increase in size increased the risk of recurrence or death by 27%, irrespective of the number of involved nodes. In parotid metastases, size thresholds of ≤3, 3-4.5 and >4.5 cm optimized prognostic discrimination. Extranodal extension (ENE) was associated with decreased DFS in nodes ≤3 cm in size (P = 0.025), but not in those >3 cm (P = 0.744). CONCLUSION: Size is an important prognostic factor in cSCCHN with parotid metastases, with optimal thresholds of ≤3, >3-4.5 and >4.5 cm. The prognostic impact of ENE was seen only in nodal metastases ≤3 cm in size. These results may have important implications for node size thresholds and inclusion of ENE in the American Joint Committee on Cancer N staging categories.

Lymphovascular invasion and risk of recurrence in papillary thyroid carcinoma.

BACKGROUND: Lymphovascular invasion (LVI) is an established adverse prognostic factor in many cancers, however, there are few studies assessing its significance in papillary thyroid carcinoma (PTC). We aimed to determine if LVI is an independent prognostic factor in PTC. METHODS: We conducted a single institution retrospective analysis of 610 patients with PTC treated between 1987 and 2016. LVI was defined as the presence or absence of cancer cells in blood vessels and/or lymphatics on histopathology. Multivariate Cox regression analysis was used to evaluate the association between LVI and recurrence-free survival (RFS). RESULTS: The study cohort included 481 (78.9%) females and 129 (21.1%) males, with a median age of 47.6 years and median follow-up of 3.4 years. LVI was present in 56 (9.2%) patients and was associated with nodal metastases (P < 0.001), extrathyroidal extension (P < 0.001), extranodal extension (P < 0.001), multifocality (P = 0.018) and microscopic positive margins (P < 0.001). On univariate analysis, LVI was associated with reduced RFS (hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.3-4.3; P = 0.007). However, after adjusting for nodal stage (pN0, pN1a, pN1b) there was no association between LVI and RFS (HR 1.3; 95% CI 0.7-2.5; P = 0.398). Similar results were obtained in full multivariate models adjusting for additional prognostic factors (HR 1.2; 95% CI 0.6-2.4; P = 0.627). CONCLUSION: LVI is strongly associated with other adverse prognostic factors in PTC, particularly the presence and extent of nodal metastases. However, after adjusting for these, LVI is not an independent predictor of recurrence.

The American Joint Committee on Cancer staging for metastatic head and neck cutaneous squamous cell carcinoma: A multi-institutional study of within-stage heterogeneity and impact on prognostic performance.

BACKGROUND: The American Joint Committee on Cancer (AJCC) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) stratifies risk poorly. We hypothesized that this results from prognostic heterogeneity within N and TNM groups. METHODS: Retrospective analysis of disease-specific survival (DSS) in a multicenter study of 1146 patients with nodal metastases from HNcSCC. RESULTS: The majority of patients were classified as pN2a or pN3b (83.1%) and TNM stage IV (90.6%). On multivariate analysis, there was statistically significant prognostic heterogeneity within these groups based on the number and size of nodal metastases, immunosuppression, and perineural invasion. When stage IV patients were categorized into low, moderate, and high-risk groups based on adverse features, there was wide variation in prognosis with 5-year DSS ranging from 90% to 60% (P < .001). CONCLUSIONS: The AJCC staging system stratifies risk poorly in HNcSCC due to significant prognostic heterogeneity within pN2a, pN3b, and stage IV groups.

Number of nodal metastases and the American Joint Committee on cancer staging of head and neck cutaneous squamous cell carcinoma: A multicenter study.

OBJECTIVES: We aimed to determine if the number of nodal metastases is an independent predictor of survival in HNcSCC, whether it provides additional prognostic information to the AJCC N and TNM stage and identify optimal cut-points for risk stratification. MATERIALS AND METHODS: Retrospective multi-institutional cohort study of patients with parotid and/or cervical nodal metastases from HNcSCC treated with curative intent by surgery ±â€¯adjuvant therapy. The impact of number of nodal metastases on disease-specific and overall survival was assessed using multivariate Cox regression. Optimal cut-points for prognostic discrimination modelled using the AIC, BIC, C-index and PVE. RESULTS: The study cohort included 1128 patients, with 962 (85.3%) males, median age of 72.9 years (range: 18-100 years) and median follow-up 3.4 years. Adjuvant radiotherapy was administered to 946 (83.9%) patients. Based on objective measures of model performance, number of nodal metastases was classified as 1-2 (N = 816), 3-4 (N = 162) and ≥5 (N = 150) nodes. In multivariate analyses, the risk of disease-specific mortality progressively increased with 3-4 nodes (HR, 1.58; 95% CI: 1.03-2.42; p = 0.036) and ≥5 nodes (HR, 2.91; 95% CI: 1.99-4.25; p < 0.001) with similar results for all-cause mortality. This simple categorical variable provided superior prognostic information to the TNM stage. CONCLUSION: Increasing number of nodal metastases is an independent predictor of mortality in HNcSCC, with categorization as 1-2, 3-4 and ≥5 nodes optimizing risk stratification and providing superior prognostic information to TNM stage. These findings may aid in the development of future staging systems as well as identification of high-risk patients in clinical trials.

Regional Metastasis in Head and Neck Cutaneous Squamous Cell Carcinoma: An Update on the Significance of Extra-Nodal Extension and Soft Tissue Metastasis.

BACKGROUND: Soft tissue metastases (STMs) are reported to predict worse prognosis than extra-nodal extension (ENE) in metastatic head and neck cutaneous squamous cell carcinoma. This study aimed to update the authors' previous analysis of STM in a larger series. METHODS: The study analyzed 535 cases of consecutive cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007. A Cox proportional hazard model was used to determine the effect of STM, with adjustment for other relevant prognostic factors. Overall survival (OS) and disease-specific survival (DSS) were the primary end points. RESULTS: Of the 535 patients, 275 (51.4%) had STM. After adjustment for the effects of age, tumor location, number of metastatic deposits, and adjuvant radiotherapy, both STM (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.08-2.22; p = 0.018) and ENE (HR, 1.56; 95% CI 1.10-2.22; p = 0.013) were shown to be independent predictors of reduced OS, with similar size of effect. CONCLUSION: In metastatic cSCC of the head and neck, STM is an independent predictor of reduced survival and has an impact on survival similar to that of ENE.

Multifocal perineural invasion is a better prognosticator than depth of invasion in oral squamous cell carcinoma.

OBJECTIVES: Prognostic significance of perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) characterized as unifocal and multifocal was compared to depth of invasion (DOI) and extranodal extension (ENE). MATERIALS AND METHODS: Univariable and multivariable analyses of 861 consecutive patients with OSCC undergoing treatment between 1995 and 2018 were performed, with local failure (LF) and disease-specific mortality (DSS) as the primary endpoints. RESULTS: After adjusting for other adverse histopathological factors and adjuvant therapy, multifocal PNI was associated with a greater risk of LF (P = .01) and DSS (P = 0.02) compared to DOI. The effect of multifocal PNI was comparable to the effect of nodal metastases without ENE (P = 0.02). LF and DSS were not improved by the administration of adjuvant radiotherapy within unifocal or multifocal PNI groups. CONCLUSION: Multifocal PNI is associated with a greater risk of death in OSCC than DOI. Its effect is comparable to that of nodal metastases (without ENE).

The extent of extrathyroidal extension is a key determinant of prognosis in T4a papillary thyroid cancer.

BACKGROUND AND OBJECTIVES: In papillary thyroid cancer (PTC), the adverse prognostic impact of extrathyroidal extension (macro-ETE) invading the subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve (T4a disease) is well established. We investigated whether the extent of macro-ETE, defined as "limited" with single structure involvement (lim-ETE) and "extensive" with multiple structures involved (ext-ETE), influences prognosis in T4a PTC. METHODS: A retrospective analysis of 610 patients with PTC identified 39 with T4a disease, including 26 with lim-ETE and 13 with ext-ETE. Univariate Cox regression was used to assess the relationship between the extent of macro-ETE and recurrence-free survival (RFS). RESULTS: Ext-ETE was associated with a five times increased risk of recurrence compared to lim-ETE (HR 5.0, P < .030), with or without adjustment for radioactive iodine administration and after adjustment for margin status (HR 4.7; P = .041). A low-risk subset of T4a disease comprising of patients aged less than 55 years with lim-ETE and clear margins accounted for one-third of the cohort and demonstrated an excellent 5-year RFS of 92%. CONCLUSIONS: The extent of macro-ETE appears to be an important determinant of prognosis in T4a PTC. A low-risk subset of T4a disease exists with an excellent prognosis.

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four-decades: Multicenter study.

BACKGROUND: This study assessed changes over time of survival of head and neck cutaneous squamous cell carcinoma (HNcSCC) with lymph node metastases. METHODS: A multicenter analysis of 1301 patients with metastatic HNcSCC treated between 1980 and 2017. Differences in disease-specific survival (DSS) and overall survival (OS) by decade were assessed using multivariate Cox regression. RESULTS: Over the study period, we noted an increase in the proportion of patients aged over 80 years (3.9%-31.7%; P < .001) and immunosuppression (1.9%-9.9%; P = .03). After adjusting for number and size of metastatic nodes, extranodal extension, perineural invasion, immunosuppression, treatment, and institution, there was a reduction in risk of cancer-related mortality from 0.47 in 1990-1999 (P = .04) to 0.30 in 2000-2009 (P < .001) when compared to 1980-1989. This remained stable at 0.30 in 2010-2017 (P = .001). OS remained stable after 1990. CONCLUSION: Despite an aging and more frequently immunosuppressed population, fewer patients are dying from metastatic HNcSCC.

Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Existing prognostic systems for metastatic cutaneous squamous cell carcinoma of the head and neck (cSCCHN) do not discriminate between the number of involved nodes beyond single versus multiple. This study aimed to determine if the number of metastatic lymph nodes is an independent prognostic factor in metastatic cSCCHN and whether it provides additional prognostic information to the American Joint Committee on Cancer (AJCC) staging. METHODS: We retrospectively analysed 101 patients undergoing curative intent treatment for metastatic cSCCHN to parotid and/or neck nodes by surgery +/- radiotherapy at Liverpool Hospital, Sydney, Australia. The impact of number of nodal metastases on disease-free survival (DFS) and risk of distant metastases was assessed using multivariate Cox regression. RESULTS: The mean number of nodal metastases was 2.5 (range 1-12). On multivariate analysis, increasing number of nodal metastases significantly predicted reduced DFS (hazard ratio 1.17; 95% confidence interval 1.05-1.30; P = 0.004), with a 17% increased risk of recurrence or death for each additional node. This remained significant in multivariate models adjusted for AJCC 8th edition nodal and TNM stages. Number of nodal metastases was also associated with risk of distant metastatic failure (hazard ratio 1.21; 95% confidence interval 1.05-1.39; P = 0.009). CONCLUSION: Increasing number of nodal metastases is associated with decreased DFS and increased risk of distant metastases in metastatic cSCCHN, with a cumulative risk increase with each additional node. It provides additional prognostic information to the AJCC staging, which may be improved by incorporating information on the number of nodal metastases beyond the current single versus multiple distinction.

Microscopic positive margins strongly predict reduced disease-free survival in pT4a papillary thyroid cancer.

BACKGROUND: Although microscopic positive margins appear to have no independent prognostic impact in papillary thyroid cancer (PTC), this may not be the case in pT4a tumors. METHODS: Retrospective analysis of 610 patients with PTC, 39 with pT4a tumors, to determine if microscopic positive margins impact disease-free survival (DFS) in pT4a PTC. RESULTS: On univariate analysis, microscopic positive margins were not associated with reduced DFS in patients with no extrathyroidal extension (ETE) (hazard ratio [HR], 1.7; P = 0.32), microscopic ETE (HR, 1.6; P = 0.36), or macroscopic ETE limited to strap muscles (HR, 1.2; P = 0.87). In contrast, microscopic positive margins were associated with reduced DFS in T4a disease (HR, 4.1; P = 0.04). Disease recurrence was nodal, distant, or biochemical, and did not occur directly at the site of positive margins. CONCLUSION: Although microscopic positive margins do not influence DFS in the majority of patients with PTC, they are associated with a fourfold increased risk of recurrence in pT4a disease.

Depth of invasion alone as an indication for postoperative radiotherapy in small oral squamous cell carcinomas: An International Collaborative Study.

BACKGROUND: We aimed to investigate whether depth of invasion (DOI) should be an independent indication for postoperative radiotherapy (PORT) in small oral squamous cell carcinomas (SCC). METHODS: Retrospective analysis of DOI (<5, 5 to <10, ≥10 mm) and disease-specific survival (DSS) in a multi-institutional international cohort of 1409 patients with oral SCC ≤4 cm in size treated between 1990-2011. RESULTS: In patients without other adverse factors (nodal metastases; close [<5 mm] or involved margins), there was no association between DOI and DSS, with an excellent prognosis irrespective of depth. In the absence of PORT, the 5-year disease-specific mortality was 10% with DOI ≥10 mm, 8% with DOI 5-10 mm, and 6% with DOI <5 mm (P = .169), yielding an absolute risk difference of only 4%. CONCLUSION: The deterioration in prognosis with increasing DOI largely reflects an association with other adverse features. In the absence of these, depth alone should not be an indication for PORT outside a clinical trial.

A critical analysis of the prognostic performance of the 8th edition American Joint Committee on Cancer staging for metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The 8th edition AJCC staging of cutaneous squamous cell carcinoma of the head and neck (cSCCHN) incorporated extranodal extension (ENE) for the first time. This study compared the prognostic performance of the 7th and 8th edition staging for cSCCHN with nodal metastases. METHODS: Retrospective analysis of 96 patients with metastatic cSCCHN, comparing the ability of staging systems to predict disease-specific and overall survival (OS) using the proportion of variation explained and Harrell's C-index. RESULTS: In AJCC8, the N classification was upstaged in 77% of patients due to the presence of ENE and 88% of patients were classified as TNM stage IV. AJCC8 was inferior to AJCC7 in predicting disease-specific survival for both N and TNM stages, and OS by TNM stage. CONCLUSIONS: The majority of patients with metastatic cSCCHN have ENE and are classified as TNM stage IV based on the 8th edition staging, resulting in poor prognostic performance.