Inflammation and ultraviolet (UV) exposure play important roles in cutaneous squamous cell carcinoma (cSCC) development and rosacea.1–3 We evaluated the relationship between personal history of rosacea with risks of cSCC by body site in the Nurses’ Health Study II (NHSII), focusing on the head and neck region given rosacea’s primary presentation in the central face.
Study participants completed biennial questionnaires that gathered medical history, including clinician-diagnosed cSCC and rosacea. Our study consisted of 90,249 white participants with no skin cancer history at baseline followed for 20 years (1991–2011) (MendeleySupplement1). Cox proportional hazard models were applied to estimate associations between history of rosacea and cSCC risk. Multivariate models were adjusted for age and other skin cancer risk factors.
During the follow-up, 577 cSCC cases were documented and confirmed by pathology reports. Baseline characteristics of study participants according to history of rosacea are described in Table 1. Rosacea was associated with statistically significant increased cSCC risk; relative risks (RR) and 95% confidence intervals were 1.40 (1.02, 1.93) (Table 2). When cSCCs were grouped by head and neck (HN) vs. non-head and neck (non-HN) sites, there was a significantly increased risk of HN cSCC (RR= 1.71[1.09, 2.69]), but no significant associations with non-HN cSCC (RR=1.21[0.78, 1.90]; p for difference=0.29). When comparing face versus non-face HN cSCCs, rosacea was associated with an increased non-face HN cSCC risk, but not with face HN cSCC (p for difference=0.32). Associations did not differ by sunscreen usage and UV exposure (MendeleySupplementaryTable1). cSCC in regions of typical rosacea outbreaks (forehead/nose/cheeks/periocular/chin) in patients with no rosacea history comprised 72.8% of total HN cSCC versus 75.0% in those with rosacea history.
Table 1.
Age-standardized baseline characteristics of study participants according to history of rosacea in the Nurses’ Health Study II, 1991
| Characteristics a | Rosacea | |
|---|---|---|
| No | Yes | |
| No. of participants | 89,163 | 1,086 |
| Age, mean (SD), y b | 36.1 (4.7) | 37.6 (4.1) |
| Family history of melanoma, % | 4.4 | 5.2 |
| Current smoker, % | 11.9 | 9.2 |
| Past smoker, % | 22.7 | 26.5 |
| Pack years, for ever smokers | 11.8 (8.6) | 10.4 (7.8) |
| Alcohol intake, mean (SD), g/d | 3.2 (6.1) | 2.9 (5.3) |
| Body mass index, mean (SD), kg/m2 | 24.6 (5.3) | 25.0 (5.9) |
| Physical activity, metabolic equivalent hours per week (SD) | 20.7 (26.5) | 18.8 (22.5) |
| Annual erythemal UV exposure at residence, mean (SD), mW/m2 | 185.6 (23.6) | 184.4 (23.3) |
| Hair color, % | ||
| Light brown | 30.4 | 33.5 |
| Dark brown/black | 39.9 | 36.7 |
| Blonde | 16.5 | 18.6 |
| Red | 3.9 | 4.2 |
| Missing | 9.3 | 7.0 |
| Skin reaction to sun, % | ||
| Burn reaction to the sun | 24.1 | 25.3 |
| Blistering burn reaction to the sun | 24.0 | 30.2 |
| Number of severe or blistering sunburns from ages 15–20, % | ||
| None | 32.8 | 30.3 |
| 1 – 2 | 39.7 | 35.5 |
| 3 – 4 | 17.2 | 19.8 |
| 5 + | 10.0 | 13.6 |
| Missing | 0.3 | 0.8 |
| Number of moles on the legs (>3 mm), % | ||
| None | 45.7 | 43.2 |
| 1 – 2 | 18.8 | 18.5 |
| 3 – 4 | 10.2 | 10.9 |
| 5 + | 21.8 | 24.1 |
| Missing | 3.5 | 3.3 |
| Physical exam, % | 89.6 | 93.1 |
| Use of sunscreen during the past summer ** , % | ||
| 0% to 50% of time | 31.8 | 27.7 |
| 75% of time | 28.2 | 30.3 |
| 100% of time | 20.6 | 26.7 |
| Missing | 19.4 | 15.3 |
Value is from 1993
Data are presented as means (SD) or medians (Q25, Q75) for continuous variables, by percentage for categorical variables, and are standardized to the age distribution of the study population, unless otherwise indicated.
Values are not age adjusted.
Table 2.
Relative risks (95% CIs) of cutaneous squamous cell carcinoma (cSCC) in relation to history of rosacea in the Nurses’ Health Study II
| Number Of cSCC (Rosacea/No Rosacea) | Age-adjusted RR (95% CI) | Multivariable-adjusted RR (95% CI)a | |
|---|---|---|---|
| Overall | 42/535 | 1.52 (1.10,2.08) | 1.40 (1.02,1.93) |
| By location b | |||
| Non-head and neck | 21/291 | 1.32 (0.85–2.06) | 1.21 (0.78–1.90) |
| Head and neck | 21/240 | 1.81 (1.15–2.84) | 1.71 (1.09–2.69)c |
| Face | 15/184 | 1.71 (1.01–2.91) | 1.61 (0.94–2.74) |
| Head and neck, not face | 6/44 | 2.69 (1.14–6.37) | 2.71 (1.13–6.46)d |
Multivariate models were adjusted for age (continuous), family history of melanoma, smoking status (never; past with <10, 10–20, 20–40, >40, or unknown pack-years; current), alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0 g/day), body mass index (<18.5, 18.5–24.9, 25–29.9, 30–34.9, ≥35, kg/cm2), quintiles of UV exposure at residence, history of severe or blistering sunburns (0, 1–2, 3–5, or ≥6), number of moles on the extremity (0,1–2, 3–4, or ≥5), skin reaction to sun exposure (not burn or blister, burn, blister), natural hair color (red/blonde, light brown, dark brown, or black), annual physical exam(yes or no) and sunscreen use during past summer (0–50%, 75% and 100%)
There was missing data that did not allow for precise determination of face vs. non-face location for all cSCC.
p = 0.29 for head and neck vs. non-head and neck SCC
p = 0.32 for face vs. head and neck, not face SCC
This was the first study evaluating associations between rosacea history and cSCC body site. The innate immune system has a role in rosacea pathogenesis. One important player is cathelicidin peptides, which have modified functions in rosacea, including modulating leukocyte chemotaxis and angiogenesis, in contrast to their typical antibiotic function in healthy skin. LL-37, a common cathelicidin in rosacea, is also upregulated in cSCC.4,5 Rosacea’s inflammatory nature may also play a part as inflammation has a significant role in cSCC development.3 Inflammation may lead to immunologic and neurovascular changes in the region that promote cSCC development. Meanwhile, patients with rosacea are advised to decrease sun exposure and many common topical rosacea treatments have anti-inflammatory effects.1 Study strengths include its prospective design, long follow-up time, ability to control for several skin cancer risk factors, and accurate ascertainment of cSCCs and tumor location. Limitations include an exclusively white female health professional cohort and lack of skin phototype, rosacea severity and subtype, and tumor staging information. Certain datapoints (e.g.sunscreen use) were only assessed once. Questionnaires included self-reported information and there may be unaccounted confounders. Number of participants with rosacea and cSCC were also small in body site analyses, limiting statistical power to detect differences of associations by body site.
These findings may support head and neck cSCC screening in rosacea patients. Further studies are warranted to confirm these associations and to determine underlying mechanisms.
Acknowledgements:
The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming.
Funding sources:
U01 CA176726, U01 HL145386
Abbreviation and acronym list:
- CI
Confidence interval
- cSCC
Cutaneous squamous cell carcinoma
- HN
Head and neck
- NHSII
Nurses’ Health Study II
- Non-HN
Non-head and neck
- RI
Rhode Island
- RR
Relative risks
- UV
Ultraviolet
Footnotes
Conflicts of interest: None.
IRB approval status: The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required.
Prior Presentation: Preliminary data from this study was presented at the 2021 Society for Investigative Dermatology Meeting.
Reprint requests: No
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