Key Points
Question
What is the risk of cutaneous squamous cell carcinoma after diagnosis of actinic keratosis (AK) during long periods of follow-up?
Findings
In this cohort study, in a community-based population in California, the risk of cutaneous squamous cell carcinoma was 1.92% per year after diagnosis of 1 or more AKs and 0.83% per year without an AK diagnosis, with older age being a stronger risk factor than AK diagnosis.
Meaning
These results can be used to develop recommendations for risk-based patient education, treatment, and surveillance.
Abstract
Importance
Risk of cutaneous squamous cell carcinoma (cSCC) after the diagnosis of actinic keratosis (AK) has not been studied during long follow-up periods.
Objective
To estimate the risk up to 10 years and identify risk factors for cSCC development.
Design, Setting, and Participants
This longitudinal cohort study, performed from January 1, 2009, to February 29, 2020, examined Kaiser Permanente Northern California patients with AK and control patients matched 1:1 on age, sex, race/ethnicity, medical center, and date of the initial diagnosis plus 30 days in the patients with AK.
Exposures
Patients with AK and control participants were followed up for up to 10 years for incidence of cSCC.
Main Outcomes and Measures
Incident cSCC was obtained from pathologic data, and subdistribution hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression analysis, accounting for competing risks, calendar year, demographic factors, and number of AKs.
Results
The study included 220 236 patients with AK and 220 236 matched control patients (mean [SD] age, 64.1 [12.2] years; 231 248 [52.5%] female). After losses to follow-up were accounted for, risk of cSCC increased with each year of follow-up by 1.92% (95% CI, 1.89%-1.95%) in patients with AK and 0.83% (95% CI, 0.81%-0.85%) in matched control patients (subdistribution HR, 1.90; 95% CI, 1.85-1.95). However, among patients 49 years or younger, those diagnosed with AK were nearly 7 times more likely to be diagnosed with cSCC than those without AK (HR, 6.77; 95% CI, 5.50-8.32). At 10 years, the cumulative incidence of cSCC reached 17.1% (95% CI, 16.9%-17.4%) in patients with AK and 5.7% (95% CI, 5.5%-5.9%) in control patients. Increased numbers of AKs were modestly associated with increased cSCC risk (≥15 AKs vs 1 AK: subdistribution HR, 1.89; 95% CI, 1.75-2.04). Older patients had much higher risk of cSCC than younger patients (compared with those ≤49 years of age at AK diagnosis; ≥80 years of age: subdistribution HR, 8.18; 95% CI, 7.62-8.78). Other than AK, risk factors for cSCC included older age, White race (a proxy for skin type), history of basal cell carcinoma, and male sex. Risk decreased between 2009 and 2019 (2018-2019 vs 2009-2010: subdistribution HR, 0.67; 95% CI, 0.63-0.72).
Conclusions and Relevance
The results of this longitudinal cohort study can be used to develop recommendations to increase early detection of cSCC. Additional research is needed to understand the effect of AK treatment on cSCC risk and outcomes of cSCC.
This cohort study estimates the risk up to 10 years and identified risk factors for cutaneous squamous cell carcinoma development in patients with actinic keratosis.
Introduction
Actinic keratoses (AKs) develop from sun exposure and affect more than 10% of the US population.1,2,3 A key risk factor for cutaneous squamous cell carcinoma (cSCC) is cumulative sun exposure.4 Although AKs are easily detected and treated, the extent to which they serve as a proxy for sun-damaged skin has not been adequately established.3 Estimates of the risk of cSCC after AK diagnosis have been based on short-term studies, and further investigation is needed to establish guidelines to standardize the frequency of skin surveillance to reduce cSCC morbidity and mortality.5 We conducted a large, community-based, matched longitudinal cohort study to assess cSCC risk for 10 years after the diagnosis of AK.
Methods
Setting
Kaiser Permanente Northern California provides care to one-third of the population of Northern California. Patients are encouraged to seek initial treatment for dermatologic conditions from their primary care practitioners, who can choose from among several modalities to consult with dermatologists.6,7 Continuing education of primary care practitioners is a priority for the dermatology department, and dermatologists provide immediate access via teledermatology to assist primary care practitioners with diagnosis and treatment while the patient is in the examination room. A clinical practice guideline for AK diagnosis and treatment is located within a web-based clinical library, and UpToDate is integrated within the electronic medical record. Most patients with relatively few AKs receive cryotherapy, whereas those with a larger number receive field therapy or both cryotherapy and field therapy. The study was approved by the local institutional review board. Informed consent was not required. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Study Design and Population
The retrospective, longitudinal cohort study included adults with an AK diagnosis (International Classification of Diseases, Ninth Revision [ICD-9] code 702.0 or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code L57.0) recorded during an in-person visit with a primary care practitioner or dermatologist from January 1, 2009, to December 31, 2019, with follow-up through February 29, 2020 (eFigure in the Supplement). We defined the index date as 30 days after the date of AK diagnosis to identify and exclude patients whose lesion was diagnosed as cSCC within 30 days. We also excluded patients without 2 years of enrollment before their AK diagnosis or who had missing information on sex or on the location where they received primary care. Finally, we excluded the small percentage who had a history of cSCC, melanoma, organ transplant, or HIV before their index date.
General health plan members without a diagnosis of AK were eligible as control patients. Control patients were selected at random and were individually matched on the index date, sex, race/ethnicity, and age of the patients with AK. We also matched on primary care medical center, a proxy for current sun exposure. Like cases, control patients were required to have continuous health plan membership for 2 years before their index date and were ineligible if they had an AK diagnosis in the 2 years preceding their index date or a history of cSCC, melanoma, HIV, or organ transplant.
Data Collection
All clinical information was obtained from the electronic medical record from 2 years before the index date to the end of follow-up. The exposure variable was the severity of sun-damaged skin. The outcome variable was the first pathologic diagnosis of cSCC.
The severity of sun-damaged skin was estimated using a proxy: the number of AKs treated within 30 days of the AK visit. For most patients (the first group), the practitioner recorded the number of AKs treated with cryotherapy as a procedure and recorded the number of lesions removed in a drop-down menu that uses 1, 2, 3 to 14, and 15 or more as response categories. A second group of patients received an AK diagnosis, but the number of lesions removed was not coded. For these patients, we used natural language processing of the clinical note, using terms linked to liquid nitrogen and cryotherapy and accounting for negation. For validation, 50 notes positive for cryotherapy and 50 notes negative for cryotherapy were manually reviewed and search terms were edited until all 100 notes were assigned correctly. We refer to this group as cryotherapy, number unspecified. A third group was diagnosed with AKs and received field therapy (fluorouracil, imiquimod, photodynamic therapy, and aminolevulinic acid) and were classified as receiving field therapy. A fourth group received both cryotherapy and field therapy and were classified as such. A fifth group was diagnosed with AKs but did not receive therapy. For this group, we reviewed a convenience sample of 10 medical records, noting that the reason for not receiving therapy was typically patient preference or a decision to wait (eg, until after a wedding). In situ and invasive cSCCs were identified using pathologic data with SNOMED codes M8070 to M8074 and M8076.8,9 To assure that the pathologic specimen was from the skin, we used natural language processing10 using the terms skin, actinic, keratosis, shave biopsy, and derm to rule out specimens from the tongue and mucosa, for example. Covariate information included age, sex, race/ethnicity, and history of a basal cell carcinoma (BCC).
Statistical Analysis
We cross-tabulated demographic characteristics between the AK and control groups to assess the closeness of matching. We used Cox proportional hazards regression with Fine and Gray competing risks to test the hypothesis that AK was associated with cSCC risk.11 Models were adjusted for 2-year period, age, sex, race/ethnicity, and history of BCC. The first proportional hazards regression model compared patients with AK (exposed) with matched control patients without AK (unexposed). A second model was similar but included a term for the interaction of age and AK status. A third model used the number of AKs treated and use of field therapy as a proxy for severity of sun-damaged skin, and patients with 2 or more treated AKs or with field therapy were compared with patients with 1 AK removed using cryotherapy. Patients were followed up from their index date to the date of cSCC diagnosis (outcome) or on the end-of-study date of February 29, 2020, death, disenrollment from the health plan, diagnosis of melanoma or HIV, or date of organ transplant. We report the subdistribution hazard ratios (HRs) and 95% CIs for the Fine and Gray model.12 The subdistribution HRs represent the relative change in the subdistribution hazard function associated with the given covariate, which can be interpreted as the relative change in the instantaneous event rate among individuals who are event free or who have experienced a competing event. The incidence of cSCC per 100 person-years (ie, percentage per year) and 95% CIs were computed by year, age, sex, race/ethnicity, and history of BCC in the AK and control cohorts using an Aalen-Johansen estimator to account for competing risks13,14 and stratifying by 10-year age group and severity of sun-damaged skin.
Results
A total of 220 236 patients with AK and 220 236 control participants were included in the study (mean [SD] age, 64.1 [12.2] years; 231 248 [52.5%] female). Inclusion and exclusion criteria are shown in the eFigure in the Supplement, and baseline characteristics are listed in Table 1.
Table 1. Baseline Characteristics of the AK Cohorta.
| Matching variable | AK cohort, % (n = 220 236) |
|---|---|
| Year | |
| 2009-2010 | 21.5 |
| 2011-2012 | 19.5 |
| 2013-2015 | 26.2 |
| 2016-2017 | 16.1 |
| 2018-2019 | 16.7 |
| Age group, y | |
| 18-49 | 12.0 |
| 50-59 | 24.3 |
| 60-69 | 33.6 |
| 70-79 | 19.4 |
| ≥80 | 10.7 |
| Sex | |
| Female | 52.5 |
| Male | 47.5 |
| Race/ethnicity | |
| African American | 0.2 |
| Asian American | 1.4 |
| Hispanic | 4.1 |
| White | 89.5 |
| Other or multiple | 4.8 |
Abbreviation: AK, actinic keratosis.
General population control patients were matched to patients with AK on year, age, sex, race/ethnicity, and medical center, and they were assigned an index date corresponding to the initial visit date plus 30 days for the patients with AK. Because their distributions of covariates were matched, they are not listed in this table.
The median length of follow-up was 4.2 years (interquartile range [IQR], 1.9-7.1 years) in the patients with AK and 3.2 years (IQR, 1.2-6.1 years) in the control patients (Table 2), and control patients were more often censored because of death or disenrollment. A total of 19 620 patients with AK (8.9%) developed cSCC compared with 7095 control patients (3.2%), for mean incidence rates of 1.92 (95% CI, 1.89-1.95) for patients with AK and 0.83 (95% CI, 0.81-0.85) for control patients per 100 person-years. After multivariable adjustment, the HR for the overall association of AK with cSCC was 1.90 (95% CI, 1.85-1.95) (Table 2). After accounting for AK status, the subdistribution HR decreased in recent years, increased sharply with age, was somewhat higher in men than women, was most pronounced among White individuals, and was increased for those with a history of BCC.
Table 2. Association of AK With cSCC in Relation to Demographic Characteristics in 220 236 Patients With AK and 220 236 Matched Control Patients.
| Characteristic | Prevalence, % | Patients with AK/control patients | Subdistribution HR (95% CI)a | |
|---|---|---|---|---|
| Follow-up, median (IQR), y | No. with cSCC | |||
| AK | 50.0 | 4.2 (1.9-7.1) | 19 620 | 1.90 (1.85-1.95) |
| Controlb | 50.0 | 3.2 (1.2-6.1) | 7095 | 1 [Reference] |
| Period of initial AK visit | ||||
| 2009-2010 | 21.5 | 9.2 (4.4-10.1)/4.8 (1.2-9.6) | 7213/2613 | 1 [Reference] |
| 2011-2012 | 19.5 | 7.4 (4.2-8.2)/7.0 (2.0-8.0) | 5411/1955 | 0.95 (0.92-0.98) |
| 2013-2015 | 26.2 | 5.0 (4.2-6.0)/4.8 (2.8-5.8) | 4727/1729 | 0.82 (0.79-0.85) |
| 2016-2017 | 16.1 | 2.9 (2.4-3.5)/2.8 (2.3-3.4) | 1654/562 | 0.76 (0.72-0.79) |
| 2018-2019 | 16.7 | 1.0 (0.5-1.5)/1.0 (0.5-1.5) | 615/236 | 0.67 (0.63-0.72) |
| Age group, y | ||||
| 18-49 | 12.1 | 4.2 (1.7-7.3)/3.8 (1.6-7.0) | 790/101 | 1 [Reference] |
| 50-59 | 24.6 | 4.6 (2.1-7.5)/3.8 (1.5-6.8) | 3056/768 | 1.97 (1.84-2.12) |
| 60-69 | 33.7 | 4.3 (1.9-7.3)/3.0 (1.1-6.0) | 6398/2421 | 3.54 (3.30-3.79) |
| 70-79 | 18.9 | 4.1 (1.8-6.9)/2.9 (1.1-5.8) | 5518/2280 | 5.78 (5.39-6.20) |
| ≥80 | 10.7 | 3.4 (1.6-5.9)/2.2 (0.8-4.5) | 3858/1525 | 8.18 (7.62-8.78) |
| Sex | ||||
| Female | 52.5 | 4.3 (1.9-7.2)/3.4 (1.4-6.4) | 9469/3306 | 1 [Reference] |
| Male | 47.5 | 4.1 (1.8-7.0)/2.9 (1.1-5.8) | 10 151/3789 | 1.40 (1.37-1.43) |
| Race/ethnicity | ||||
| African American | 0.2 | 4.3 (2.3-7.0)/4.2 (1.9-6.9) | 8/0 | 0.15 (0.07-0.29) |
| Asian American | 1.4 | 4.0 (1.8-6.7)/3.8 (1.7-6.6) | 66/10 | 0.19 (0.15-0.24) |
| Hispanic | 4.1 | 4.0 (1.7-6.9)/3.8 (1.6-6.8) | 535/58 | 0.45 (0.42-0.49) |
| White | 89.5 | 4.2 (1.9-7.2) /3.1 (1.2-6.0) | 18 106/6873 | 1 [Reference] |
| Other or multiple | 4.8 | 4.2 (1.9-7.0)/3.6 (1.5-6.7) | 905/154 | 0.69 (0.65-0.73) |
| History of BCC | ||||
| Yes | 12.8 | 4.1 (1.8-6.9)/2.3 (0.8-4.9) | 6396/1279 | 1.83 (1.78-1.89) |
| No | 87.2 | 4.3 (1.9-7.2)/3.3 (1.3-6.2) | 13 224/5816 | 1 [Reference] |
Abbreviations: AK, actinic keratosis; BCC, basal cell carcinoma; cSCC, cutaneous squamous cell carcinoma; HR, hazard ratio; IQR, interquartile range.
The Cox proportional hazards regression model includes year of AK visit, age, sex, race/ethnicity, and history of BCC as coded in the table.
General population control patients were matched to patients with AK on year, age, sex, race/ethnicity, and medical center, and they were assigned an index date corresponding to the initial visit date plus 30 days for the patients with AK.
We generated a second model to examine whether the association of AK with cSCC was different in younger and older persons by introducing an interaction term for AK status and age group (results not tabulated). Younger persons with an AK diagnosis had a greater HR of cSCC than older persons with an AK diagnosis. Thus, patients 49 years or younger who had AKs were nearly 7 times more likely than those without AKs to develop cSCC during the study period (HR, 6.77; 95% CI, 5.50-8.32). For those 50 to 59 years of age, the subdistribution HR was 3.20 (95% CI, 2.96-3.64), whereas the subdistribution HR was less than 2.00 for older patients (P < .001 for interaction).
A third model restricted to patients with AK examined the association of severity of sun-damaged skin with risk of cSCC (Table 3). Approximately one-third of patients who received treatment for AK had 1 AK removed, whereas more than half of cSCC cases occurred in patients with 1 or 2 AKs. In those who received cryotherapy, cSCC risk increased somewhat in relation to the number of lesions removed (≥15 AKs vs 1 AK: subdistribution HR, 1.89; 95% CI, 1.75-2.04), whereas risk in those who received field therapy was intermediate.
Table 3. Association of Severity of Sun-Damaged Skin With cSCC in 220 236 Patients With 19 620 Cases of cSCC .
| Proxy for severity of sun-damaged skin | Prevalence, %a | Follow-up, median (IQR), y | No. of patients with a cSCC | Proportion of total cSCCs, % | cSCC incidence per 100 person-years (95% CI) | Subdistribution HR (95% CI)b |
|---|---|---|---|---|---|---|
| No. of AKs removed with cryotherapy | ||||||
| 1 | 35.5 | 4.4 (2.0-7.4) | 5503 | 28.0 | 1.47 (1.43-1.51) | 1 [Reference] |
| 2 | 19.3 | 4.9 (2.3-7.8) | 4807 | 24.5 | 2.22 (2.15-2.28) | 1.30 (1.25-1.36) |
| 3-14 | 11.3 | 4.1 (1.8-6.8) | 3338 | 17.0 | 2.93 (2.83-3.03) | 1.55 (1.49-1.62) |
| ≥15 | 2.0 | 4.7 (2.1-7.2) | 751 | 3.8 | 3.52 (3.27-3.77) | 1.89 (1.75-2.04) |
| Cryotherapy, No. unspecified | 18.6 | 3.5 (1.6-6.2) | 2535 | 12.9 | 1.53 (1.47-1.59) | 1.09 (1.04-1.14) |
| Field therapy | 2.9 | 3.4 (1.4-6.7) | 558 | 2.8 | 2.11 (1.94-2.29) | 1.42 (1.30-1.55) |
| Cryotherapy and field therapy | 4.8 | 3.5 (1.5-6.6) | 1267 | 6.5 | 2.84 (2.69-3.00) | 1.83 (1.72-1.95) |
| No therapyc | 5.6 | 4.3 (1.9-7.2) | 861 | 4.4 | 1.50 (1.40-1.60) | 1.05 (0.97-1.13) |
Abbreviations: AK, actinic keratosis; BCC, basal cell carcinoma; cSCC, cutaneous squamous cell carcinoma; HR, hazard ratio; IQR, interquartile range.
The analysis is restricted to patients with AK and does not include general population control patients.
The Cox proportional hazards regression model includes year of AK visit, age, sex, race/ethnicity, and history of BCC as coded in Table 2.
We reviewed a convenience sample of 10 medical records from this group, noting that the reason for not receiving therapy was typically patient preference or a decision to wait (eg, until after a wedding). The numbers of AKs in this group were not recorded systematically and could not be analyzed.
The cumulative incidence of cSCC associated with the severity of sun-damaged skin is given in Table 4 and the Figure after age stratification. Among those with AK, the cumulative incidence of cSCC reached 10% at 7 to 8 years for patients in their 50s, 5 to 6 years for patients in their 60s, 3 to 4 years for patients in their 70s, and 1 to 2 years for patients in their 80s. At 10 years, the cumulative incidence of cSCC reached 17.1% (95% CI, 16.9%-17.4%) in patients with AK and 5.7% (95% CI, 5.5%-5.9%) in control patients. Table 4 reports the cumulative incidence of cSCC for patients with AK compared with patients without AK in every age stratum.
Table 4. Crude Cumulative Incidence Rates (per 100 Persons) of Incident cSCC by Age Among 440 472 KPNC Members 18 Years or Older, 2009-2019.
| Variable | Crude cumulative incidence rates (95% CI) by age, y | ||||
|---|---|---|---|---|---|
| 18-49 | 50-59 | 60-69 | 70-79 | ≥80 | |
| Patients with AK | |||||
| No. | 26 531 | 53 507 | 73 961 | 42 693 | 23 544 |
| Time since index date, y | |||||
| 0 | 0.4 (0.4-0.5) | 0.9 (0.8-1.0) | 1.5 (1.4-1.6) | 2.4 (2.2-2.5) | 4.1 (3.8-4.3) |
| 1 | 0.9 (0.8-1.0) | 1.9 (1.8-2.0) | 3.1 (2.9-3.2) | 4.7 (4.5-5.0) | 7.7 (7.3-8.0) |
| 2 | 1.4 (1.2-1.5) | 2.9 (2.8-3.1) | 4.6 (4.4-4.8) | 7.1 (6.8-7.3) | 10.7 (10.3-11.1) |
| 3 | 2.1 (1.9-2.3) | 4.0 (3.8-4.2) | 6.2 (6.0-6.4) | 9.6 (9.3-9.9) | 13.6 (13.1-14.1) |
| 4 | 2.8 (2.6-3.1) | 5.3 (5.1-5.5) | 8.0 (7.7-8.2) | 12.1 (11.8-12.5) | 15.9 (15.4-16.5) |
| 5 | 3.4 (3.1-3.7) | 6.6 (6.4-6.9) | 9.9 (9.6-10.2) | 14.7 (14.3-15.1) | 18.0 (17.4-18.6) |
| 6 | 4.3 (4.0-4.7) | 7.9 (7.6-8.2) | 11.7 (11.4-12.1) | 17.0 (16.5-17.5) | 19.7 (19.1-20.3) |
| 7 | 5.2 (4.8-5.7) | 9.2 (8.9-9.6) | 13.7 (13.3-14.0) | 19.3 (18.7-19.8) | 21.3 (20.7-22.0) |
| 8 | 6.4 (5.9-7.0) | 10.6 (10.2-11.1) | 15.9 (15.5-16.3) | 21.6 (21.0-22.2) | 22.5 (21.8-23.2) |
| 9 | 7.4 (6.8-8.1) | 12.0 (11.5-12.5) | 17.6 (17.1-18.1) | 23.6 (22.9-24.3) | 23.4 (22.7-24.1) |
| 10 | 8.2 (7.4-9.0) | 13.4 (12.7-14.2) | 19.3 (18.6-20.0) | 25.9 (24.9-27.0) | 23.9 (23.1-24.7) |
| Matched control patients without AK | |||||
| No. | 26 531 | 53 507 | 73 961 | 42 693 | 23 544 |
| Time since index date, y | |||||
| 0 | 0.0 (0.0-0.1) | 0.4 (0.3-0.5) | 1.3 (1.2-1.4) | 2.4 (2.3-2.6) | 2.9 (2.7-3.1) |
| 1 | 0.1 (0.1-0.2) | 0.7 (0.6-0.8) | 2.1 (2.0-2.2) | 3.8 (3.6-4.0) | 4.5 (4.3-4.8) |
| 2 | 0.2 (0.2-0.3) | 1.0 (0.9-1.0) | 2.8 (2.7-2.9) | 4.8 (4.5-5.0) | 5.6 (5.3-6.0) |
| 3 | 0.3 (0.2-0.4) | 1.2 (1.1-1.3) | 3.4 (3.2-3.5) | 5.6 (5.4-5.9) | 6.4 (6.1-6.8) |
| 4 | 0.4 (0.3-0.5) | 1.5 (1.4-1.7) | 3.9 (3.7-4.1) | 6.3 (6.0-6.6) | 7.0 (6.6-7.3) |
| 5 | 0.4 (0.4-0.6) | 1.9 (1.7-2.0) | 4.5 (4.3-4.7) | 7.1 (6.8-7.4) | 7.5 (7.1-7.9) |
| 6 | 0.6 (0.5-0.7) | 2.2 (2.0-2.3) | 5.0 (4.8-5.2) | 7.7 (7.3-8.0) | 7.8 (7.4-8.2) |
| 7 | 0.6 (0.5-0.8) | 2.4 (2.2-2.6) | 5.5 (5.2-5.7) | 8.3 (7.9-8.7) | 8.1 (7.7-8.5) |
| 8 | 0.9 (0.7-1.2) | 2.7 (2.4-2.9) | 6.0 (5.8-6.3) | 8.7 (8.3-9.1) | 8.4 (8.0-8.8) |
| 9 | 1.0 (0.8-1.3) | 2.9 (2.6-3.2) | 6.6 (6.2-6.9) | 9.0 (8.6-9.4) | 8.6 (8.2-9.1) |
| 10 | 1.2 (0.9-1.5) | 3.2 (2.9-3.6) | 7.0 (6.5-7.5) | 9.6 (8.8-10.4) | 8.7 (8.2-9.2) |
| P valuea | <.001 | <.001 | <.001 | <.001 | <.001 |
Abbreviations: AK, actinic keratosis; cSCC, cutaneous squamous cell carcinoma, Kaiser Permanente Northern California.
The Gray test for equality of cumulative incidence functions of cSCC was used for patients with AK and matched control patients.
Figure. Ten-Year Cumulative Incidence of Cutaneous Squamous Cell Carcinoma by Age and Severity of Sun-Damaged Skin.
The index date is defined as 30 days after the date of actinic keratosis diagnosis (for patients with actinic keratosis), which is also the date of matching (for control patients). The data account for loss to follow-up. Compared with Table 3, the number of categories was reduced by combining cryotherapy of 3 to 14 lesions and 15 or more lesions, combining field therapy and field therapy with cryotherapy, removing cryotherapy with unknown number of lesions, and removing no therapy.
Discussion
In 220 236 patients with AK and 220 236 general population control patients observed for up to 10 years, cSCC incidence rates were 1.92% per year after an AK diagnosis and 0.83% per year without an AK diagnosis. Age was more strongly associated with cSCC risk compared with AK diagnosis, and larger numbers of AKs were only modestly associated with increasing cSCC risk. However, age modified the association of AK with cSCC risk; therefore, among persons 18 to 49 years of age, those with an AK had a nearly 7-fold increased risk of cSCC compared with those who did not. The time from AK diagnosis to 10% risk of SCC was shortest in the oldest patients and in patients with more AKs or who received field therapy. In addition, this study found that after age and length of follow-up were carefully accounted for, the 2018-2019 cohort had only two-thirds the risk of the 2008-2009 cohort, suggesting improvements in primary prevention in more recent birth cohorts.
Limitations
Limitations of the study included the use of clinical and not histologic diagnosis of AK and use of AK treatment information as a proxy for sun damage. In addition, some control patients may have had undiagnosed AK, which would have biased the subdistribution HR of 1.90 (95% CI, 1.85-1.95) for the association of any AK with cSCC risk upward, although the analysis of number of AKs (Table 3) would not be affected. To increase the feasibility of the study, AK diagnoses recorded after the start of follow-up were not assessed or solar elastosis identified, which is underrecorded in this setting. Information on skin type beyond race/ethnicity was lacking, which likely confounded the associations for Hispanic patients. Furthermore, some AK cases may be misdiagnosed. Regarding generalizability, Kaiser Permanente’s community-based population is well characterized and largely representative of the underlying population. In addition, although the study excluded patients with immune-mediated diseases, an analysis of these patients was recently published by Kaiser Permanente.15
This report is comparable to past reports,16,17 which also observed higher risk with age, in men, and in relation to AK. It is not clear whether AKs transform to cSCC or merely indicate sun-damaged skin3,17,18,19,20 with increased potential to develop cSCC. Studies have not adequately estimated AK regression and progression rates. In a 2013 systematic review,3 spontaneous regression of an AK lesion ranged from 15% to 63%, recurrence of AK from 15% to 53%, and progression of a single AK to an cSCC at the same anatomical location from 0% to 0.53% per year. This study treated AK as a marker of sun-damaged skin.
Conclusions
It is best practice to educate patients about the role of repeated sun exposure in damaging the skin and causing solar elastosis, AK, and skin cancer. Reducing sun exposure appears to be effective in that the incidence of skin cancer has decreased for more recent birth cohorts.21 Regarding skin examinations to detect cSCC, current recommendations by the US Preventive Services Task Force state that “there is insufficient evidence for any population that regular visual skin examination by a clinician can reduce skin cancer–related morbidity and mortality...”22(p 433) The relative effectiveness and safety of watchful waiting, cryotherapy, and field therapy for treating AKs have not been adequately studied.23,24,25,26 The American Academy of Dermatology is currently developing AK guidelines.27 Patients who decide not to receive treatment for an AK should be informed about the signs of progression and when to contact a practitioner.
eFigure. Design of the Retrospective, Longitudinal Cohort Study
References
- 1.Bickers DR, Lim HW, Margolis D, et al. ; American Academy of Dermatology Association; Society for Investigative Dermatology . The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500. doi: 10.1016/j.jaad.2006.05.048 [DOI] [PubMed] [Google Scholar]
- 2.Ratushny V, Gober MD, Hick R, Ridky TW, Seykora JT. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J Clin Invest. 2012;122(2):464-472. doi: 10.1172/JCI57415 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169(3):502-518. doi: 10.1111/bjd.12420 [DOI] [PubMed] [Google Scholar]
- 4.Kim JYS, Kozlow JH, Mittal B, Moyer J, Olenecki T, Rodgers P; Work Group; Invited Reviewers . Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018;78(3):560-578. doi: 10.1016/j.jaad.2017.10.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Werner RN, Stockfleth E, Connolly SM, et al. ; International League of Dermatological Societies; European Dermatology Forum . Evidence- and consensus-based (S3) guidelines for the treatment of actinic keratosis—International League of Dermatological Societies in cooperation with the European Dermatology Forum—Short Version. J Eur Acad Dermatol Venereol. 2015;29(11):2069-2079. doi: 10.1111/jdv.13180 [DOI] [PubMed] [Google Scholar]
- 6.Marwaha SS, Fevrier H, Alexeeff S, et al. Comparative effectiveness study of face-to-face and teledermatology workflows for diagnosing skin cancer. J Am Acad Dermatol. 2019;81(5):1099-1106. doi: 10.1016/j.jaad.2019.01.067 [DOI] [PubMed] [Google Scholar]
- 7.Dusendang JR, Marwaha S, Alexeeff SE, et al. Association of teledermatology workflows with standardising co-management of rashes by primary care physicians and dermatologists. J Telemed Telecare. 2020;1357633X20930453. doi: 10.1177/1357633X20930453 [DOI] [PubMed] [Google Scholar]
- 8.Eide MJ, Krajenta R, Johnson D, et al. Identification of patients with nonmelanoma skin cancer using health maintenance organization claims data. Am J Epidemiol. 2010;171(1):123-128. doi: 10.1093/aje/kwp352 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Wang W, Jorgenson E, Ioannidis NM, Asgari MM, Whittemore AS. A prediction tool to facilitate risk-stratified screening for squamous cell skin cancer. J Invest Dermatol. 2018;138(12):2589-2594. doi: 10.1016/j.jid.2018.03.1528 [DOI] [PubMed] [Google Scholar]
- 10.Liu L, Shorstein NH, Amsden LB, Herrinton LJ. Natural language processing to ascertain two key variables from operative reports in ophthalmology. Pharmacoepidemiol Drug Saf. 2017;26(4):378-385. doi: 10.1002/pds.4149 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat.1988;16(3):1141-1154. doi: 10.1214/aos/1176350951 [DOI] [Google Scholar]
- 12.Austin PC, Fine JP. Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med. 2017;36(27):4391-4400. Published online September 15, 2017. doi: 10.1002/sim.7501 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Aalen OO, Johansen S. An empirical transition matrix for nonhomogeneous Markov chains based on censored observations. Scan Stat Theory Appl. 1978;5(3):141-150. https://www.jstor.org/stable/4615704 [Google Scholar]
- 14.Example 64.12: Model assessment using cumulative sums of Martingale residuals. In: SAS/STAT(R) 9.2 User’s Guide. 2nd ed. Accessed June 21, 2019. https://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.htm#statug_phreg_sect043.htm
- 15.Gunawardane ND, Dontsi M, Lyon LL. Risk of non-melanoma skin cancer in connective tissue disease and the impact of immunosuppressive therapy. J Drugs Dermatol. 2020;19(5):519-523. doi: 10.36849/JDD.2020.4781 [DOI] [PubMed] [Google Scholar]
- 16.Foote JA, Harris RB, Giuliano AR, et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer. 2001;95(1):7-11. doi: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lee JH, Kim YH, Han KD, et al. Incidence of actinic keratosis and risk of skin cancer in subjects with actinic keratosis: a population-based cohort study. Acta Derm Venereol. 2018;98(3):382-383. doi: 10.2340/00015555-2854 [DOI] [PubMed] [Google Scholar]
- 18.Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988;1(8589):795-797. doi: 10.1016/S0140-6736(88)91658-3 [DOI] [PubMed] [Google Scholar]
- 19.Lanoue J, Chen C, Goldenberg G. Actinic keratosis as a marker of field cancerization in excision specimens of cutaneous malignancies. Cutis. 2016;97(6):415-420. [PubMed] [Google Scholar]
- 20.Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42(1, pt 2):23-24. doi: 10.1067/mjd.2000.103339 [DOI] [PubMed] [Google Scholar]
- 21.Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013;68(6):957-966. doi: 10.1016/j.jaad.2012.11.037 [DOI] [PubMed] [Google Scholar]
- 22.US Preventive Services Task Force. Recommendation statement: screening for skin cancer. JAMA. 2016;316:429-435. doi: 10.1001/jama.2016.8465 [DOI] [PubMed] [Google Scholar]
- 23.Jansen MHE, Kessels JPHM, Nelemans PJ, et al. Randomized trial of four treatment approaches for actinic keratosis. N Engl J Med. 2019;380(10):935-946. doi: 10.1056/NEJMoa1811850 [DOI] [PubMed] [Google Scholar]
- 24.Neugebauer R, Su KA, Zhu Z, et al. Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. J Am Acad Dermatol. 2019;80(4):998-1005. doi: 10.1016/j.jaad.2018.11.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gupta AK, Paquet M, Villanueva E, Brintnell W. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12(12):CD004415. doi: 10.1002/14651858.CD004415.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Khanna R, Bakshi A, Amir Y, Goldenberg G. Patient satisfaction and reported outcomes on the management of actinic keratosis. Clin Cosmet Investig Dermatol. 2017;10:179-184. doi: 10.2147/CCID.S121323 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.American Academy of Dermatology Association. Clinical guidelines. Accessed February 22, 2021. https://www.aad.org/member/clinical-quality/guidelines
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Supplementary Materials
eFigure. Design of the Retrospective, Longitudinal Cohort Study