Factors Predictive of Recurrence and Death From Cutaneous Squamous Cell Carcinoma: A 10-Year, Single-Institution Cohort Study
TL;DR: Tumor diameter of at least 2 cm, invasion beyond fat, poor differentiation, perineural invasion, and ear, temple, or anogenital location were risk factors associated with poor outcomes in primary cutaneous squamous cell carcinoma.
Abstract: Importance Although most cases of cutaneous squamous cell carcinoma (CSCC) are easily cured with surgery or ablation, a subset of these tumors recur, metastasize, and cause death. We conducted the largest study of CSCC outcomes since 1968. Objective To identify risk factors independently associated with poor outcomes in primary CSCC. Design A 10-year retrospective cohort study. Setting An academic hospital in Boston. Participants Nine hundred eighty-five patients with 1832 tumors. Main Outcomes and Measures Subhazard ratios for local recurrence, nodal metastasis, disease-specific death, and all-cause death adjusted for presence of known prognostic risk factors. Results The median follow-up was 50 (range, 2-142) months. Local recurrence occurred in 45 patients (4.6%) during the study period; 36 (3.7%) developed nodal metastases; and 21 (2.1%) died of CSCC. In multivariate competing risk analyses, independent predictors for nodal metastasis and disease-specific death were a tumor diameter of at least 2 cm (subhazard ratios, 7.0 [95% CI, 2.2-21.6] and 15.9 [4.8-52.3], respectively), poor differentiation (6.1 [2.5-14.9] and 6.7 [2.7-16.5], respectively), invasion beyond fat (9.3 [2.8-31.1] and 13.0 [4.3-40.0], respectively), and ear or temple location (3.8 [1.1-13.4] and 5.9 [1.3-26.7], respectively). Perineural invasion was also associated with disease-specific death (subhazard ratio, 3.6 [95% CI, 1.1-12.0]), as was anogenital location, but few cases were anogenital. Overall death was associated with poor differentiation (subhazard ratio, 1.3 [95% CI, 1.1-1.6]) and invasion beyond fat (1.7 [1.1-2.8]). Conclusions and Relevance Cutaneous squamous cell carcinoma carries a low but significant risk of metastasis and death. In this study, patients with CSCC had a 3.7% risk of metastasis and 2.1% risk of disease-specific death. Tumor diameter of at least 2 cm, invasion beyond fat, poor differentiation, perineural invasion, and ear, temple, or anogenital location were risk factors associated with poor outcomes. Accurate risk estimation of outcomes from population-based data and clinical trials proving the utility of disease-staging modalities and adjuvant therapy is needed.
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TL;DR: AJCC's 8th edition of the Staging manual, Head and Neck Section, introduced significant modifications from the prior 7th edition as discussed by the authors, including the reorganization of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck-specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph
Abstract: Answer questions and earn CME/CNE The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior seventh edition. This article details several of the most significant modifications, and the rationale for the revisions, to alert the reader to evolution of the field. The most significant update creates a separate staging algorithm for high-risk human papillomavirus-associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer with other causes. Other modifications include: the reorganizing of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck-specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph node category (N) in all but the viral-related cancers and mucosal melanoma. The Head and Neck Task Force worked with colleagues around the world to derive a staging system that reflects ongoing changes in head and neck oncology; it remains user friendly and consistent with the traditional tumor, lymph node, metastasis (TNM) staging paradigm. CA Cancer J Clin 2017;67:122-137. © 2017 American Cancer Society.
1,046 citations
TL;DR: Estimates of the 2012 incidence, nodal metastasis, and death from invasive CSCC are based on previous estimates of incidence and outcomes of CSCC, and are an underrecognized health issue.
Abstract: Background It is estimated that over 700,000 new cases of cutaneous squamous cell carcinoma (CSCC) are diagnosed annually in the United States. However, CSCC has been excluded from national cancer registries. Thus the precise incidence of CSCC, along with metastases and deaths resulting from it, is unknown. Objective We sought to estimate the 2012 incidence of invasive (non-in situ) CSCC and the number of nodal metastases and deaths arising from it in the US white population. Methods US studies reporting incidence of CSCC, or the number of nodal metastases or deaths arising from it, were reviewed. Linear regression was used to estimate current CSCC incidence based on available incidence data adjusting for higher reported incidences in southern versus northern/central United States. Reported risks of nodal metastases and death from CSCC were averaged. Averages were used to estimate current metastasis and death rates based on incidence estimates. The number of estimated CSCC deaths was compared against deaths from other cancers. Results It is estimated that 186,157 to 419,543 whites were given a diagnosis of CSCC, 5604 to 12,572 developed nodal metastasis, and 3932 to 8791 died from CSCC in the United States in 2012. Limitations The estimates of the 2012 incidence, nodal metastasis, and death from invasive CSCC are based on previous estimates of incidence and outcomes of CSCC. Conclusion CSCC is an underrecognized health issue. In the central and southern United States, deaths from CSCC may be as common as deaths from renal and oropharyngeal carcinomas, and melanoma. Population-based studies reporting CSCC incidence and outcomes are required to verify these estimates.
625 citations
TL;DR: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes, which improve the foundation for understanding this disease and should aid in identifying and treating aggressive cS CC.
Abstract: Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Experimental Design: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Results: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53 , CDKN2A , NOTCH1 , AJUBA , HRAS , CASP8 , FAT1 , and KMT2C ( MLL3 ). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2 , PARD3 , and RASA1 , were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. Conclusions: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR .
457 citations
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...1% risk of disease-specific death (5)....
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TL;DR: The recently published 8th edition TNM classification institutes the following changes to the staging of head and neck: new stage classifications [HPV-related oropharyngeal cancer (HPV+ OPC) and soft tissue sarcoma of theHead and neck (HN-STS)] and modification of T and N categories.
Abstract: The main purpose of the TNM system is to provide an anatomic-based classification to adequately depict cancer prognosis. Accurate cancer staging is important for treatment selection and outcome prediction, research design, and cancer control activities. To maintain clinical relevance, periodical updates to TNM are necessary. The recently published 8th edition TNM classification institutes the following changes to the staging of head and neck (excluding thyroid cancer): new stage classifications [HPV-related oropharyngeal cancer (HPV+ OPC) and soft tissue sarcoma of the head and neck (HN-STS)] and modification of T and N categories [T and N categories for nasopharyngeal cancer (NPC), T categories for oral cavity squamous cell carcinomas (OSCC), N categories for non-viral related head and neck cancer and unknown primary (CUP), and T categories for head and neck cutaneous carcinoma]. These changes reflect better understanding tumor biology and clinical behavior (e.g., HPV+ OPC and HN-STS), improved outcomes associated with technical advances in diagnosis and treatment (e.g., NPC), evolving knowledge about additional prognostic factors and risk stratification from research and observation (e.g., inclusion of depth of invasion variable for OSCC, inclusion of extranodal extension variable for all non-viral head and neck cancer, and reintroduction of size criteria for non-Merkel cell cutaneous carcinoma of the head and neck). This review summarizes the changes and potential advantages and limitations/caveats associated with them. Further evidence is needed to evaluate whether these changes would result in improvement in TNM stage performance to better serve the needs for clinical care, research, and cancer control.
387 citations
National and Kapodistrian University of Athens1, Paris Diderot University2, Université libre de Bruxelles3, Catholic University of the Sacred Heart4, German Cancer Research Center5, Medical University of Graz6, Versailles Saint-Quentin-en-Yvelines University7, National Institute for Health Research8, Odense University Hospital9, Aix-Marseille University10
TL;DR: The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours and a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics.
370 citations
References
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TL;DR: This article proposes methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation, but these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function.
Abstract: With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function In this article we pro
11,109 citations
TL;DR: This book complements the other references well, and merits a place on the bookshelf of anyone concerned with the analysis of lifetime data from any eld.
Abstract: (2003). The Statistical Analysis of Failure Time Data. Technometrics: Vol. 45, No. 3, pp. 265-266.
4,600 citations
TL;DR: In this article, the authors proposed a regression model for failure time distributions in the context of counting process models and showed that the model can be used to estimate the probability of failure.
Abstract: Preface.1. Introduction.1.1 Failure Time Data.1.2 Failure Time Distributions.1.3 Time Origins, Censoring, and Truncation.1.4 Estimation of the Survivor Function.1.5 Comparison of Survival Curves.1.6 Generalizations to Accommodate Delayed Entry.1.7 Counting Process Notation.Bibliographic Notes.Exercises and Complements.2. Failure Time Models.2.1 Introduction.2.2 Some Continuous Parametric Failure Time Models.2.3 Regression Models.2.4 Discrete Failure Time Models.Bibliographic Notes.Exercises and Complements.3. Inference in Parametric Models and Related Topics.3.1 Introduction.3.2 Censoring Mechanisms.3.3 Censored Samples from an Exponential Distribution.3.4 Large-Sample Likelihood Theory.3.5 Exponential Regression.3.6 Estimation in Log-Linear Regression Models.3.7 Illustrations in More Complex Data Sets.3.8 Discrimination Among Parametric Models.3.9 Inference with Interval Censoring.3.10 Discussion.Bibliographic Notes.Exercises and Complements.4. Relative Risk (Cox) Regression Models.4.1 Introduction.4.2 Estimation of beta.4.3 Estimation of the Baseline Hazard or Survivor Function.4.4 Inclusion of Strata.4.5 Illustrations.4.6 Counting Process Formulas. 4.7 Related Topics on the Cox Model.4.8 Sampling from Discrete Models.Bibliographic Notes.Exercises and Complements.5. Counting Processes and Asymptotic Theory.5.1 Introduction.5.2 Counting Processes and Intensity Functions.5.3 Martingales.5.4 Vector-Valued Martingales.5.5 Martingale Central Limit Theorem.5.6 Asymptotics Associated with Chapter 1.5.7 Asymptotic Results for the Cox Model.5.8 Asymptotic Results for Parametric Models.5.9 Efficiency of the Cox Model Estimator.5.10 Partial Likelihood Filtration.Bibliographic Notes.Exercises and Complements.6. Likelihood Construction and Further Results.6.1 Introduction.6.2 Likelihood Construction in Parametric Models.6.3 Time-Dependent Covariates and Further Remarks on Likelihood Construction.6.4 Time Dependence in the Relative Risk Model.6.5 Nonnested Conditioning Events.6.6 Residuals and Model Checking for the Cox Model.Bibliographic Notes.Exercises and Complements.7. Rank Regression and the Accelerated Failure Time Model.7.1 Introduction.7.2 Linear Rank Tests.7.3 Development and Properties of Linear Rank Tests.7.4 Estimation in the Accelerated Failure Time Model.7.5 Some Related Regression Models.Bibliographic Notes.Exercises and Complements.8. Competing Risks and Multistate Models.8.1 Introduction.8.2 Competing Risks.8.3 Life-History Processes.Bibliographic Notes.Exercises and Complements.9. Modeling and Analysis of Recurrent Event Data.9.1 Introduction.9.2 Intensity Processes for Recurrent Events.9.3 Overall Intensity Process Modeling and Estimation.9.4 Mean Process Modeling and Estimation.9.5 Conditioning on Aspects of the Counting Process History.Bibliographic Notes.Exercises and Complements.10. Analysis of Correlated Failure Time Data.10.1 Introduction.10.2 Regression Models for Correlated Failure Time Data.10.3 Representation and Estimation of the Bivariate Survivor Function.10.4 Pairwise Dependency Estimation.10.5 Illustration: Australian Twin Data.10.6 Approaches to Nonparametric Estimation of the Bivariate Survivor Function.10.7 Survivor Function Estimation in Higher Dimensions.Bibliographic Notes.Exercises and Complements.11. Additional Failure Time Data Topics.11.1 Introduction.11.2 Stratified Bivariate Failure Time Analysis.11.3 Fixed Study Period Survival Studies.11.4 Cohort Sampling and Case-Control Studies.11.5 Missing Covariate Data.11.6 Mismeasured Covariate Data.11.7 Sequential Testing with Failure Time Endpoints.11.8 Bayesian Analysis of the Proportional Hazards Model.11.9 Some Analyses of a Particular Data Set.Bibliographic Notes.Exercises and Complements.Glossary of Notation.Appendix A: Some Sets of Data.Appendix B: Supporting Technical Material.Bibliography.Author Index.Subject Index.
3,596 citations
TL;DR: All studies since 1940 on the prognosis of squamous cell carcinoma of the skin and lip are reviewed, finding local recurrences occur less frequently when SCC is treated by Mohs micrographic surgery.
Abstract: We reviewed all studies since 1940 on the prognosis of squamous cell carcinoma (SCC) of the skin and lip. The following variables are correlated with local recurrence and metastatic rates: (1) treatment modality, (2) prior treatment, (3) location, (4) size, (5) depth, (6) histologic differentiation, (7) histologic evidence of perineural involvement, (8) precipitating factors other than ultraviolet light, and (9) host immunosuppression. Local recurrences occur less frequently when SCC is treated by Mohs micrographic surgery. This local recurrence rate differential in favor of Mohs micrographic surgery holds true for primary SCC of the skin and lip (3.1% vs 10.9%), for ear SCC (5.3% vs 18.7%), for locally recurrent (previously treated) SCC (10% vs 23.3%), for SCC with perineural involvement (0% Ys 47%), for SCC of size greater than 2 cm (25.2% vs 41.7%), and for SCC that is poorly differentiated (32.6% vs 53.6%).
1,346 citations
Additional excerpts
...Follow-up, y 1 1832 (30) 2 1569 (12) 3 1312 (6) 4 1064 (1) 5 835 (0) 6 612 (1) 7 430 (0)...
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TL;DR: The 1994 nonmelanoma skin cancer incidence in the United States is updated to reflect the growth and changing age distribution of the population and the increases in age-adjusted incidence rates documented in two population-based studies.
Abstract: Because death from nonmelanoma skin cancer is uncommon, quantification of its morbidity is particularly important. Although its incidence is increasing rapidly, the most recent nationwide estimates are 16 years old. The purpose of this study was to estimate the 1994 nonmelanoma skin cancer incidence in the United States. We updated the 16-year-old incidence estimates to reflect the growth and changing age distribution of the population and the increases in age-adjusted incidence rates documented in two population-based studies. The projected 1994 incidence of nonmelanoma skin cancer in the United States is 900,000 to 1,200,000 cases, similar in magnitude to the overall incidence of noncutaneous cancers. Nonmelanoma skin cancer imposes an enormous public health burden on the U.S. population. Quantification of its morbidity and its prevention are important priorities.
1,069 citations
Additional excerpts
...Follow-up, y 1 1832 (3) 2 1596 (5) 3 1342 (6) 4 1090 (3) 5 856 (1) 6 625 (1) 8 285 (0) 7 440 (2) 96...
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...Follow-up, y 1 1832 (30) 2 1569 (12) 3 1312 (6) 4 1064 (1) 5 835 (0) 6 612 (1) 7 430 (0)...
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