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.
Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of cutaneous epithelium, represents 20% to 50% of skin cancers. Although the majority of cSCCs are successfully eradicated by ...surgical excision, a subset of cSCC possesses features associated with a higher likelihood of recurrence, metastasis, and death. The proper identification of these aggressive cSCCs can guide additional work-up and management. In the first article in this continuing medical education series, we discuss the incidence, recurrence rates, mortality rates, and risk factors associated with cSCC and review the staging systems used to stratify patients into high- and low-risk groups. The second article in this series reviews the treatment options for cSCC, with focused attention on the management of high-stage tumors.
Field cancerization was first described in 1953 when pathologic atypia was identified in clinically normal tissue surrounding oropharyngeal carcinomas. The discovery of mutated fields surrounding ...primary tumors raised the question of whether the development of subsequent tumors within the field represented recurrences or additional primary tumors. Since this initial study, field cancerization has been applied to numerous other epithelial tissues, including the skin. Cutaneous field cancerization occurs in areas exposed to chronic ultraviolet radiation, which leads to clonal proliferations of p53-mutated fields and is characterized by multifocal actinic keratoses, squamous cell carcinomas in situ, and cutaneous squamous cell carcinomas. In the first article in this continuing medical education series, we define field cancerization, review the available grading systems, and discuss the epidemiology, risk factors, and outcomes associated with this disease.
While the majority of cutaneous squamous cell carcinomas (cSCCs) can be treated surgically, the additional work-up and treatments indicated for high-risk cSCC remain undefined. In recent years, ...improvements in tumor staging systems have allowed for the more accurate stratification of tumors into high- and low-risk categories. This insight, along with the publication of cSCC guidelines, brings us closer to the development of a consensus approach. The second article in this continuing medical education series addresses in question and answer format the most common questions related to advanced and high-stage cSCCs, with a simplified flowchart. The questions include the following: 1) Does my patient have high-risk cSCC?; 2) What is the next step for patients with cSCC and palpable lymphadenopathy?; 3) In patients with no clinically evident lymphadenopathy, who are candidates for lymph node staging?; 4) What forms of radiologic imaging can help detect subclinical lymph node metastases?; 5) What is the role of sentinel lymph node biopsy in cSCC?; 6) Which patients with cSCC need adjuvant radiation therapy?; 7) Is adjuvant chemotherapy an option for patients with high-stage cSCC after surgery?; 8) Are targeted and immunologic therapies an option for advanced cSCC?; 9) How often should I follow up with my patient after he/she has been diagnosed with a high-risk cSCC?; 10) What are the options for chemoprophylaxis in a patient with an increased risk of cSCC?; and 11) What chemopreventive measures can be started in coordination with medical oncology or transplant physicians?
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.
To identify risk factors independently associated with poor outcomes in primary CSCC.
A 10-year retrospective cohort study.
An academic hospital in Boston.
Nine hundred eighty-five patients with 1832 tumors.
Subhazard ratios for local recurrence, nodal metastasis, disease-specific death, and all-cause death adjusted for presence of known prognostic risk factors.
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).
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.
No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is ...high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.
We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.
In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval CI, 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.
Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).
This study proposes an alternative tumor staging system for cutaneous squamous cell carcinoma (CSCC) that more precisely defines the small subset of tumors with a high risk of metastasis and death.
...To identify risk factors for poor outcomes in CSCC and evaluate the 2010 American Joint Committee on Cancer (AJCC) tumor (T) staging system's ability to stratify occurrence of these outcomes.
Retrospective cohort study.
A single academic hospital.
Study participants were identified via a pathology and dermatopathology database search for patients diagnosed as having high-risk CSCC.
Two hundred fifty-six primary high-risk CSCCs were included. Outcomes for AJCC tumor stages T2 to T4 were statistically indistinguishable because only 4 cases (<2% of the cohort) were AJCC stages T3 or T4, which require bone invasion. Subsequently, the bulk of poor outcomes (83% of nodal metastases, 92% of deaths from CSCC) occurred in AJCC stage T2 cases. An alternative tumor staging system was developed with the aim of better stratifying this stage T2 group. Four risk factors were found to be statistically independent prognostic factors for at least 2 outcomes of interest in multivariate modeling. These factors (poor differentiation, perineural invasion, tumor diameter ≥2 cm, invasion beyond subcutaneous fat) were incorporated in the alternative staging with 0 factors indicating T1, 1 factor indicating T2a; 2 to 3 factors, T2b; and 4 factors or bone invasion, T3. Stages T2a and T2b significantly differed in incidences of all 4 end points. Stage T2b tumors comprised only 19% of the cohort but accounted for 72% of nodal metastases and 83% of deaths from CSCC.
The proposed alternative tumor staging system offers improved prognostic discrimination via stratification of stage T2 tumors. Validation in other cohorts is needed. Meanwhile, stage T2b tumors are responsible for most poor outcomes and may be a focus of high-risk CSCC study.
Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor ...prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma.
This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498.
Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1–15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32–55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia.
Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care.
Regeneron Pharmaceuticals and Sanofi.
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