Trends in cutaneous squamous cell carcinoma on the lip incidence and mortality in the United States, 2000–2019

Abstract

Objective:

This study provided a systematic analysis of the trend in incidence and incidence-based mortality for cutaneous squamous cell carcinoma (cSCC) on the lips in the USA using demographic characteristics from the Surveillance, Epidemiology, and End Results (SEER) database.

Methods:

Patients diagnosed with cSCC on the lips between 2000 and 2019 from the 17 registries of the USA were identified. Incidence and incidence-based mortality rates were analyzed using SEER*Stat 8.4.0.1 software. This paper calculated incidence rates and incidence-based mortality rates by 100,000 person-years for sex, age, race, SEER registries, median household income ($/year), rural-urban distribution, and primary site. The annual percent changes (APC) in incidence and incidence-based mortality rates were then calculated using joinpoint regression software.

Results:

Among 8,625 patients diagnosed with cSCC on the lips from 2000 to 2019, men (74.67%), white (95.21%), and 60–79 years old were the most common population, and 3,869 deaths from cSCC on the lips occurred. The overall incidence of cSCC on the lips was 0.516 per 100,000 person-years. cSCC on the lip incidence rates were highest among men, white, and patients aged 60–79 years old. cSCC on the lip incidence rates decreased by 3.210%/year over the study period. The incidence of cSCC on the lips has been decreasing in all sexes, ages, high- or low-income households, and urban or rural patients. The overall incidence-based mortality rate of cSCC on the lips during 2000–2019 was 0.235 per 100,000 person-years. cSCC on the lip incidence-based mortality rates were highest among men, whites, and people older than 80 years old. cSCC on the lip incidence-based mortality increased by 4.975%/year over the study period. cSCC on the lip incidence-based mortality rates increased for all sexes, races, ages, primary sites, high- or low-income households, and urban or rural patients during the study period.

Conclusion:

Among patients in the USA diagnosed with cSCC on the lips from 2000 to 2019, the overall incidence decreased by 3.210% annually, and incidence-based mortality increased by 4.975%/year. These findings update and supplement the epidemiological information of cSCC on the lips in the USA.

1 Introduction

Cutaneous squamous cell carcinoma (cSCC) is a malignant proliferation of the skin epithelium that accounts for 20% to 50% of skin cancers and is the second most common nonmelanoma skin cancer (NMSC) or keratinocytic carcinoma (1–6). cSCC occurs mainly in the head and neck, and more than 50% of newly diagnosed lesions occur in this area (7).

During 2002–2007, the age-standardized incidence rate of cSCC in Europe was nine to 96 cases per 100,000 men and five to 68 cases per 100,000 women (8). According to statistics from 2002, the incidence rate of cSCC in Australia in 2011 was about 499 cases per 100,000 men and 291 cases per 100,000 women, and the mortality rate was two cases per 100,000 people (5). The incidence rate of CSCC in Spain is 40 cases per 100,000 person-years (8). Whereas, the US National Tumor Registry did not include cSCC, and exact US incidence and mortality rates cannot be derived.

The risk factors for cSCC include exposure to the sun, age, fair skin, and immunosuppression (3, 5, 9–11). cSCC is more common in white people and men, with a ratio of 3:1. The incidence rate increased with age, with the median age of onset over 60 years old. Despite a lower prevalence among Hispanic, black, and Asian patients, cSCC is the most common form of skin cancer in these populations. The mortality of cSCC in black patients can be as high as 18% due to delayed diagnosis and poor prognosis (2–5). Most cSCC can be successfully resolved by surgical operation, while some cSCC are at high risk for recurrence, metastasis, and death (12, 13). cSCC on the lips is considered a high-risk skin cancer with a metastasis rate of 11% compared to 1% for other sites. cSCC become a public health problem due to the adverse outcomes it causes.

Therefore, this study provided a systematic analysis of the trend in incidence and the incidence-based mortality for cSCC on the lips in the USA using demographic characteristics from the Surveillance, Epidemiology, and End Results (SEER) database.

2 Method

2.1 Data sources

This research used the SEER*Stat 8.4.0.1 software to obtain data on cSCC on the lip cases diagnosed during 2000–2019 from SEER-17 registries (“Incidence - SEER Research Data, 17 Registries, November 2021 Sub (2000–2019)”). The SEER-17 Incidence-Based Mortality database provides a convenient and intuitive mechanism for analyzing cSCC on the lip mortality from death certificates (14). In contrast to general mortality rates, incidence-based mortality allows for the classification of deaths based on variables related to cancer occurrence.

2.2 Analysis population

This research included patients who were diagnosed with cSCC on the lips between the years 2000 and 2019. Cases were determined by selecting squamous cell tumors (codes 8050-8089) and primary sites on the lips (codes C00.0-00.3, 00.6, 44.0). Demographic characteristics analyzed in this study includes the following variables: sex, race, age at diagnosis (0–19, 20–39, 40–59, 60–79, and 80 years or older) or age at death in the case of incidence-based mortality calculation, SEER registries, median household income ($/year), rural-urban distribution, and primary site.

2.3 Statistical analysis

The SEER*stat version 8.4.0.1 software was used to calculate the incidence and incidence-based mortality rates of cSCC on the lips. All rates were adjusted to the 2000 US standard population and expressed by 100,000 person-years. We then used the National Cancer Institute’s Joinpoint Regression program, version 4.9.1.0, to calculate the annual percentage changes (APCs) and 95% confidence intervals (CIs) (15). The Joinpoint Regression software analyzed rates over time and detected significant changes in APCs, then selected the best model with the minimum number of joinpoints and calculated p-values using t-tests. All statistical tests were two-sided, and p-values less than 0.05 were considered statistically significant.

3 Results

3.1 Baseline characteristics

Between the years 2000 and 2019, 8,625 cases diagnosed as cSCC on the lips in the states recorded by SEER-17 were included in the incidence analysis (Table 1). Most patients were men (74.67%), white (95.21%), 60–79 years old (47.14%), and with an external lower lip (80.60%). Incidence-based mortality analysis revealed that, from 2000 to 2019, 3,869 patients with cSCC on the lips died, of whom 2,870 (74.18%) cases were men, 3,773 (97.52%) were white patients, 3,588 (92.8%) were over 60 years old, and 3,115 (80.51%) were external lower lips.

3.2 Incidence rates and trends over time

The overall incidence of cSCC on the lips during 2000–2019 was 0.516 (95% CI, 0.505 to 0.527) per 100,000 person-years. cSCC on the lip incidence rates were highest among men (0.867 (95% CI, 0.845 to 0.888)), white (0.437 (95% CI, 0.034 to 0.055)), patients 60–79 years old (1.856 (95% CI, 1.799 to 1.914)), and external lower lip patients (0.415 (95% CI, 0.406 to 0.425)). When compared to states in the SEER-17 registries, the incidence was the highest in Iowa (1.183 (95% CI, 1.104 to 1.266)) and the lowest in Alaska Natives (0.051 (95% CI, 0.001 to 0.307)) (Table 1).

cSCC on the lip incidence rates decreased by −3.210% (95% CI, −3.994 to −2.420; p < 0.001) per year over the study period, with an incidence rate of 0.022 in 2000 and 0.294 in 2019 per 100,000 person-years (Table 2). Rates did not decrease significantly during 2005–2009 (APC = −0.774%, (95% CI, −3.539 to 2.07; p = 0.446)) and 2010–2014 (APC = −3.396% (95% CI, −2.766 to 2.032; p = 0.636)) but decreased by −13.153% (95% CI, −17.558 to −8.513; p = 0.003) per year during 2015–2019. The incidence of cSCC on the lips has been decreasing in all sex and ages (Figure 1). From 2000 to 2019, there was a significant downward trend in the incidence rates for high- or low-income households, urban or rural patients, and external lower lip patients (APC = −3.766% (95% CI, −4.596 to −2.929; p < 0.001)). Among low-income households, the incidence rate decreased significantly from 2000 to 2004 (APC = −6.210% (95% CI, −9.715 to −2.568; p = 0.013]) and among high-income households, from 2005 to 2009 (APC = −6.362% (95% CI, −11.184 to −1.278; p = 0.029)). In urban areas, there was a significant decrease in prevalence in 2000–2004 (APC = −6.245% (95% CI, −10.608 to −1.668; p = 0.023)) and 2015–2019 (APC = −12.574% (95% CI, −17.555 to −7.293; p = 0.005)); in rural areas in 2015–2019 (APC = −15.288% (95% CI, −25.641 to −3.494; p = 0.027)), the incidence rate also decreased significantly. The incidence has been decreasing in most subgroups of SEER registries except for Seattle (Puget Sound) and Utah. However, it has not changed recently among blacks and Asians or Pacific Islanders and decreased significantly among whites (APC = −3.136% (95% CI, −3.978 to −2.287; p = 0.030)).

Figure 1

3.3 Incidence-based mortality rates and trends over time

The overall incidence-based mortality rate of cSCC on the lips during 2000–2019 was 0.235 (95% CI, 0.227 to 0.242) per 100,000 person-years. cSCC on the lip incidence-based mortality rates were highest among men (0.442 (95% CI, 0.426 to 0.459%)), whites (0.276 (95% CI, 0.268 to 0.285)), people older than 80 years old (4.016 (95% CI, 3.851 to 4.186)), and external lower lip patients (0.189 (95% CI, 0.182 to 0.195)). When compared to states in the SEER-17 registries, incidence-based mortality was highest in Hawaii (0.832 (95% CI, 0.055 to 0.122)) and lowest in Alaska Natives (0 (95% CI, 0 to 0.219)).

cSCC on the lip incidence-based mortality increased by 4.975% (95% CI, 2.942 to 7.048; p < 0.001) per year over the study period (Table 3). cSCC on the lip incidence-based mortality rates increased for all sexes, races, and ages during the study period (Figure 2). High-income (APC = 4.782 [95% CI, 2.810–6.792, p < 0.001)), low-income (APC = 5.856 (95% CI, 3.471–8.296; p < 0.001)), urban (APC = 4.732 (95% CI, 2.663 to 6.843; p < 0.001)), rural (APC = 6.331 (95% CI, 3.877 to 8.842; p < 0.001]) patients, external upper lip (APC = 5.154 (95% CI, 2.362 to 8.022; p = 0.001)), and external lower lip (APC = 4.909 (95% CI, 2.911 to 6.945; p < 0.001)) showed a significant increase in mortality. In urban areas, there was a significant increase in morbidity-based mortality in 2000–2004 (APC = 37.693 (95% CI, 0.675 to 88.322; p = 0.047)) and a significant decrease in morbidity-based mortality in 2015–2019 (APC = −0.732 (95% CI, −1.244 to −0.218; p = 0.02)).

Figure 2

4 Discussion

The lips are the anatomical junction of two distinct groups of cancers. Lip squamous cell carcinoma (lip SCC) is more aggressive than cSCC but less aggressive than oral mucosal squamous cell carcinoma (16). The external lower lip was the location with the highest risk of metastasis (17, 18). Therefore, this study was conducted to systematically analyze the trends in incidence and incidence-based mortality for cSCC on the lips using the SEER database.

Since the 1980s, researchers have demonstrated that UVR can cause skin damage and increase the risk of skin cancer. In 1992, the International Agency for Research on Cancer classified solar radiation as the first category of carcinogenic hazard, which is known to cause human cancer. In 2009, the World Health Organization classified UVR tanning devices as a Group I carcinogen based on evidence related to indoor tanning and an increased risk of skin cancer (19).

This study mainly found that the age-adjusted incidence rate of cSCC on the lips decreased significantly from 2000 to 2019, while the incidence-based mortality rate increased significantly. People with fair skin have less melanin and less protection against UVR (20–22). Consistent with the results of previous studies, cSCC on the lips was most common in white people (22) and less common in black people, Indians, and Asians (23, 24). It is more common in men than in women, with a male-to-female ratio of up to 4:1 (22, 25). The high incidence in men may be related to the fact that men were exposed to the sun for a relatively long time for working (26). Women have more knowledge of skincare and sun protection, use sunscreen lotion, and seek shade more frequently than men (27). The decrease in incidence in men may be due to the strengthening of sun protection education, the increase in the proportion of wearing sun protection clothing, and the increase in the number of people using sunscreen (28, 29).

The reduction of the incidence rate may also be influenced by other factors. Actinic keratosis (AK) is considered a precancerous lesion caused by prolonged exposure of the skin to UVR and is one of the most common causes of dermatologic treatment, which can progress to invasive cSCC (30, 31). Advanced age, fair skin, and prolonged sun exposure are major risk factors for AK (32, 33). The incidence of AK was increasing due to extended life expectancy and inappropriate sun exposure behaviors. Although the exact prevalence of AK is unknown, it affects 1%–44% of the adult population worldwide (32). There were more than 3,500 new cases of lip cancer in the USA, 90% of which were cSCC. A recent study showed that the prevalence of AC was 31.3% among people over 45 years old in northwestern Spain (34). The treatments for AK include cryotherapy, topical treatments with or without photodynamic therapy (PDT), and surgery and laser therapy which are less used (32). The actual definition of AK remains controversial; it is also defined as carcinoma in situ by some experts. AC (35) is a precursor of cSCC on the lips (36). Similar to AK, AC is a precancerous lesion caused by prolonged sun exposure or UVR that is most commonly on the lower lip along the vermilion border. Other risk factors include increasing age, especially over 60 years, working outdoors for more than 25 years, or a history of NMSC (37). The prevalence of AC is higher in people with fair skin and in areas with high UV exposure near the equator. Men have a higher incidence of AC than women, probably because they are exposed to relatively more sunlight and use less lip balm and cosmetics (38).

The improvement of awareness of precancerous lesions, early diagnosis abilities, and more timely treatment methods can cure precancerous lesions at an early stage and prevent precancerous lesions from developing into cSCC. The reduced incidence may be associated with this. Immunosuppression is a high-risk factor for cSCC, which may lead to the development of invasive cancer and the metastasis of cSCC (10–13, 39–42). Patients with kidney or heart transplantation are 65 times more likely to develop cSCC than general populations (41). In recent years, the use of immunomodulators in the treatment of autoimmune diseases, allergic diseases, and cancer has become popular (43–46). This may also be one of the factors leading to the increase in mortality. The increase in mortality may also be related to the aging of the population and the prolongation of the lifespan of patients with chronic diseases (47). cSCC on the lips is considered a high-risk skin cancer with a metastasis probability of 11%, compared to 1% for other body sites (36), making it critical to identify and appropriately manage these potentially malignant precursor lesions.

cSCC on the lips is prevalent in people over 40 years of age, with the highest incidence in 60–79 years, and incidence-based morbidity increases over 80 years old. The elderly were relatively vulnerable, and the 5-year disease-specific survival rate of patients aged over 75 years old, especially those over aged 85 years old, is relatively poor (23). A study has found that old age is not a risk factor for poorer survival in metastatic cSCC on the lips, which might be limited to metastatic cSCC on the lips disease (48). The trend analysis in this study reflected the high morbidity of both metastatic and nonmetastatic disease in elderly patients. There were more risk factors in elderly patients that may lead to high incidence and mortality in elderly patients (25). Elderly patients are more likely to suffer from tumors with large tumor diameters, low differentiation, deep tumor invasion, and more lymph node metastasis than young people. The risk of postoperative complications is high in elderly patients, with large postoperative defects and difficult wound healing. The poor mobility and weakness of the elderly make regular follow-up more difficult and the prognosis worse (25, 49).

Incidence and incidence-based mortality rates were higher among low-income and rural dwellers than among high-income and urban dwellers. Skin cancer was also a major economic burden in the USA (19). The cost of treating melanoma and NMSC was estimated at $1.7 billion per year (50, 51). The cost of lost productivity was estimated to be $3.8 billion (52). Prevention and early detection are effective ways to reduce the burden of disease and the cost of treatment (19, 53). A study conducted in Minnesota, USA, found that compared with urban dwellers, rural dwellers spent more time outdoors, used sun lotion less frequently, and had less awareness of sun protection (54). There were higher standards of education and income in urban dwellers than rural dwellers (42). Whites and people with high education levels know more about skin cancer and sunscreen, including using sunscreen, looking for shade, and wearing sunscreen clothes (27, 42, 55).

There are several limitations to this study. Some clinical data, such as tobacco and alcohol intake (39), staging and grading information, tumor depth (56), immunosuppression, HPV status, and family history of skin cancer, were lacking in the SEER database, thus limiting the ability of our results to exactly reflect the national patient population. Therefore, there may be a bias in the clinicopathological characteristics of tumors and specific risk factors for a poorer prognosis. The distribution of cases throughout race, age, and geographic regions is not equally represented. These restrictions should be kept in mind when using data collected through these registries. Nevertheless, the SEER database provides powerful statistical capabilities in evaluating the demographic characteristics of cSCC on the lips. Multicentered effort and additional risk factors are needed to further understand the incidence and incidence-based mortality of cSCC on the lips.

This study analyzed trends in incidence and incidence-based mortality in patients with cSCC on the lips from 2000 to 2019 and update and supplemented the epidemiological information on this type of cutaneous cancer. The incidence and incidence-based mortality in patients with cSCC on the lips were decreasing, but the mortality rate was increasing. The decrease in incidence might be related to the improvement of sun protection awareness with the increase in income and education levels, as well as timely diagnosis and treatment of precancerous lesions, thus preventing further deterioration of cSCC. The decline in men’s incidence was related to the improvement in male sunscreen protection awareness. The increased mortality may be related to the aging of the population and the use of immunosuppressive drugs that lead to the development of cSCC into invasive cancer.

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