Is bariatric surgery associated with skin cancer incidence in patients with obesity?
In this nonrandomized controlled trial of 4047 participants in the Swedish Obese Subjects study, bariatric surgery was associated with reduced incidence of skin cancer, including melanoma.
The findings suggest that bariatric surgery is associated with a reduction in the incidence of skin cancer, including melanoma, in patients with obesity and that there may be an association between obesity and this cancer form.
Obesity is a cancer risk factor, and bariatric surgery in patients with obesity is associated with reduced cancer risk. However, evidence of an association among obesity, bariatric surgery, and skin cancer, including melanoma, is limited.
To investigate the association of bariatric surgery with skin cancer (squamous cell carcinoma and melanoma) and melanoma incidence.
Design, Setting, and Participants
This nonrandomized controlled trial, the Swedish Obese Subjects (SOS) study, is ongoing at 25 surgical departments and 480 primary health care centers in Sweden and was designed to examine outcomes after bariatric surgery. The study included 2007 patients with obesity who underwent bariatric surgery and 2040 contemporaneously matched controls who received conventional obesity treatment. Patients were enrolled between September 1, 1987, and January 31, 2001. Data analysis was performed from June 29, 2018, to November 22, 2018.
Patients in the surgery group underwent gastric bypass (n = 266), banding (n = 376), or vertical banded gastroplasty (n = 1365). The control group (n = 2040) received the customary treatment for obesity at their primary health care centers.
Main Outcomes and Measures
The SOS study was cross-linked to the Swedish National Cancer Registry, the Cause of Death Registry, and the Registry of the Total Population for data on cancer incidence, death, and emigration.
The study included 4047 participants (mean [SD] age, 47.9 [6.1] years; 2867 [70.8%] female). Information on cancer events was available for 4042 patients. The study found that bariatric surgery was associated with a markedly reduced risk of melanoma (adjusted subhazard ratio, 0.43; 95% CI, 0.21-0.87; P = .02; median follow-up, 18.1 years) and risk of skin cancer in general (adjusted subhazard ratio, 0.59; 95% CI, 0.35-0.99; P = .047). The skin cancer risk reduction was not associated with baseline body mass index or weight; insulin, glucose, lipid, and creatinine levels; diabetes; blood pressure; alcohol intake; or smoking.
Conclusions and Relevance
The results of this study suggest that bariatric surgery in individuals with obesity is associated with a reduced risk of skin cancer, including melanoma.
ClinicalTrials.gov identifier: NCT01479452
The incidence of malignant melanoma in fair-skinned populations has increased steadily for decades, faster than for any other cancer.1,2 Although the 5-year survival rate has improved during the same period partly because of the introduction of immunotherapy, in the United States only, the number of deaths from melanoma increased from 8650 in 2009 to an estimated 10 130 in 2016.3,4 Despite extensive research, a need still exists for increased understanding of mechanisms and risk factors underlying melanoma.
Obesity is an established risk factor for several cancer types,5,6 but the association between obesity and melanoma is inconclusive.7 Increasing evidence from human and murine models suggests that obesity is a risk factor for squamous cell carcinoma (SCC) and melanoma, the 2 most common skin cancer types.8,9 High consumption of fat may be associated with increased risk of SCC tumor, particularly in people with a history of skin cancer.10 Obesity and skin pigmentation are genetically associated and share common susceptibility genes.8 Obese mice and mice with diet-induced obesity display larger melanoma tumors and higher rates of melanoma metastasis compared with mice with normal body weights.8 Furthermore, fat cells in deep skin layers secrete hormones, cytokines, chemokines, free fatty acids, and other lipids, and these factors have been suggested to be associated with skin tumor growth.9
Bariatric surgery is the most effective treatment for sustainable weight loss in patients with obesity, and it reduces the risk of morbidity and mortality.11-14 In addition, bariatric surgery has been shown to reduce cancer risk in patients with obesity.15-17 In 2009, bariatric surgery was reported to be associated with reduced cancer incidence in the Swedish Obese Subjects (SOS) study.18 However, the low incidence of specific cancer diagnoses at that time made it impossible to draw firm conclusions on skin cancer risk. With a median follow-up time of 18.1 years, there are now sufficient numbers of skin cancer events. The aim of this study was to investigate the association between bariatric surgery and skin cancer, including melanoma.
Study Design and Treatment
This nonrandomized controlled trial, the SOS study, is an ongoing, prospective, and matched intervention trial that compares bariatric surgery with conventional obesity treatment.13,19 The trial flow diagram is presented in Figure 1, and details on study design and recruitment are given in the eAppendix in the Supplement. Patients were recruited to the SOS study between September 1, 1987, and January 31, 2001. Data analysis was performed from June 29, 2018, to November 22, 2018. Seven regional ethics review boards approved the SOS study protocol, and informed consent (oral and written) was obtained from all participants.
A per-protocol approach was used in all analyses; thus, all participants were included in their original study group until any bariatric surgery was performed in the control group or there was a change in or removal of the bariatric surgical procedure in the surgery group, after which they were censored from the analysis. We identified participants who switched groups by using the National Patient Register and SOS questionnaires (at baseline and follow-up visits). In the surgery per-protocol group (n = 2007), participants underwent gastric bypass (n = 266), banding (n = 376), or vertical banded gastroplasty (n = 1365). The control group (n = 2040) received the customary treatment for obesity at their primary health care centers. Inclusion criteria were age of 37 to 60 years and a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) greater than 38 for women and greater than 34 for men. Exclusion criteria were identical in the surgery and control groups and were minimal, aimed at obtaining an operable surgical group. The intervention began on the day of surgery for the surgically treated individual and the matched control. Surgery and control participants underwent a baseline examination approximately 4 weeks before the start of the intervention. Thereafter, clinical examinations were performed after 0.5, 1, 2, 3, 4, 6, 8, 10, 15, and 20 years. Centralized biochemical examinations were performed at matching and baseline examinations and after 2, 10, 15, and 20 years. Questionnaires were completed at every clinical examination.
The primary end point of the study was overall mortality,13 and the secondary end points were diabetes,19 gallbladder disease,20 and cardiovascular disease.14 The outcomes of the current study, skin cancer incidence and melanoma incidence, were not predefined end points.
Baseline characteristics were obtained from the clinical examination, questionnaires, and centralized blood chemical analyses. Baseline alcohol intake was calculated from dietary questionnaires, as previously described.21 Smoking was defined as a positive answer to the question, “Do you smoke daily?” Data on cancer incidence, death, and emigration were obtained by cross-checking Social Security numbers from the SOS database with the Swedish National Cancer Registry, the Cause of Death Registry, and the Registry of the Total Population, respectively. The Swedish National Cancer Registry has more than 95% coverage for all tumors of which 99% are morphologically verified.22 To capture all skin tumor events in the cohort, codes 190 and 191 according to the International Classification of Diseases, Seventh Revision (ICD-7) or codes 172 and 173 according to the International Classification of Diseases, Ninth Revision (ICD-9) were included. No basal cell carcinomas were included in the study. When melanoma skin tumors were analyzed separately, codes 190 (ICD-7) and 172 (ICD-9) were used. The cutoff date for the current report was December 31, 2013.
Data for all baseline characteristics are reported as mean (SD). A 2-sided P ≤ .05 was considered to be statistically significant. Statistical analyses were performed using Stata, version 12.1 (StataCorp). Cumulative incidence of skin cancer and incidence of malignant melanoma were estimated with competing risk regression models in which deaths from causes other than skin cancer or melanoma were treated as competing events. The cumulative incidence functions are presented as Figure 2 and Figure 3. The relative treatment effect in the bariatric surgery group compared with the control group was evaluated in a primary unadjusted analysis with a single covariate for the treatment group (surgery or control) and is expressed as a subhazard ratio from the competing risk regression. Calculation of the 95% CI for the number needed to treat was based on the bootstrap method with 5000 replications of individuals sampled with replication. To assess the baseline differences between the surgery and control groups, analyses were adjusted for the following baseline confounders: sex, age, BMI, alcohol, and smoking status. No adjustments were made for multiple comparisons. In addition, sensitivity analyses based on propensity score methods were conducted to evaluate the effects of potential confounders.
In the interaction analysis, the incidence rates were calculated in subgroups defined by risk factors at baseline. The subgroups were based on insulin levels, blood glucose levels, presence of diabetes, body weight, BMI, systolic and diastolic blood pressure, serum triglyceride levels, serum high-density lipoprotein cholesterol level, serum cholesterol level, serum creatinine level, alcohol intake, and smoking status at baseline. The association of bariatric surgery with the incidence of cancer events was tested by including the corresponding interaction term (ie, product of type of treatment [surgery or control] and the corresponding continuous variable) in the competing risk regression model.
The study included 4047 participants (mean [SD] age, 47.9 [6.1] years; 2867 [70.8%] female). The surgery group underwent gastric bypass (265 [13.2%]), banding (376 [18.7%]), or vertical banded gastroplasty (1369 [68.1%]). The control group received conventional treatment for obesity at their primary health care center, ranging from advanced lifestyle advice to no professional treatment.23 The Table gives the baseline characteristics of the 2 groups. Patients in the surgery group were a mean of 1 year younger than the patients in the control group, but the surgery group had greater amounts of most other metabolic risk factors. After bariatric surgery, the mean (SD) weight loss was 28.7 (14.3) kg at the 2-year follow-up visit, 21.1 (15.1) kg at the 10-year follow-up visit, and 21.6 (16.6) kg at the 15-year follow-up visit. The mean (SD) weight changes in the control group were small and never exceeded 3 kg in gain or loss (eFigure 1 in the Supplement). The relative weight loss between the surgery and control group groups was 23.7% (95% CI, 23.1%-24.3%) at year 2, 19.5% (95% CI, 18.5%-20.4%) at year 10, and 18.9% (95% CI, 17.6%-20.2%) at year 15. Information on cancer incidence was available for 4042 of the 4047 participants in the cohort. Median follow-up time was 18.1 years (interquartile range, 14.8-20.9 years; maximum, 26 years).
During the follow-up period, 16 SCC events and 29 melanoma events occurred in the control group and 11 SCC and 12 melanoma events in the surgery group. In a pooled analysis, the first-time skin cancer events (SCC and melanoma combined) in the 2 groups were analyzed. The incidence rates for skin cancer were 1.2 per 1000 person-years (95% CI, 0.9-1.6 per 1000 person-years) in the control group and 0.7 per 1000 person-years (95% CI, 0.4-1.0 per 1000 person-years) in the surgery group (Figure 2). The subhazard ratio with surgery was 0.59 (95% CI, 0.35-0.99; P = .047) compared with the control group after adjusting for sex, age, BMI, smoking, and alcohol intake. The unadjusted hazard ratio for SCC with surgery was 0.65 (95% CI, 0.30-1.39), but this finding was not statistically significant (eFigure 2 in the Supplement). On the basis of 29 malignant melanoma events in the control group and 12 in the surgery group, the incidence rates were 0.8 per 1000 person-years (95% CI, 0.6-1.2 per 1000 person-years) in the control group and 0.3 per 1000 person-years (95% CI, 0.2-0.6 per 1000 person-years) in the surgery group (Figure 3). The adjusted subhazard ratio between the surgery and control groups was 0.43 (95% CI, 0.21-0.87; P = .02). The number needed to treat to prevent 1 malignant melanoma event during 20 years with bariatric surgery was 106 (95% CI, 54-440). A total of 655 deaths (16.2%) among the 4047 study participants were treated as competing events in the analyses of skin cancer and melanoma. Results remained essentially unchanged after analyses based on different propensity score adjustments and matching (eTable 1 in the Supplement). In patients with melanoma, the number of deaths attributed to melanoma was 7 in the control group and 2 in the surgery group.
When we stratified the analysis by sex, 22 women with melanoma were in the control group and 9 women with melanoma were in the surgery group (hazard ratio, 0.38; 95% CI, 0.18-0.83; P = .02). In addition, 7 men with melanoma were in the control group and 3 men with melanoma were in the surgery group (hazard ratio, 0.41; 95% CI, 0.10-1.60; P = .20). No differences were found in the surgical treatment benefit between the subgroups by baseline BMI, body weight, insulin level, blood glucose level, presence of diabetes, systolic or diastolic blood pressure, serum triglyceride levels, serum high-density lipoprotein cholesterol level, serum cholesterol level, serum creatinine level, alcohol intake, or smoking (eTable 2 in the Supplement).
These findings suggest that bariatric surgery is associated with reduced incidence of skin cancer (SCC and melanoma combined) and melanoma in individuals with obesity. However, bariatric surgery should not be viewed as a public health intervention specific to skin cancer. Instead, these findings give additional support for an association between obesity and skin cancer and for an association between weight loss and reduced cancer incidence.
Of importance, baseline BMI was not associated with the preventive effect of bariatric surgery on skin cancer incidence. It is possible that the reduced skin cancer risk after surgery is associated with altered metabolic or endocrine processes after bariatric surgery. In line with this possibility, a previous study24 found that baseline insulin levels are associated with reduced cancer incidence in women after bariatric surgery. Moreover, bariatric surgery may reduce circulating cancer-associated biomarkers related to inflammation, cell proliferation, and angiogenesis.25
Well-described risk factors for melanoma include fair skin, hair, and eye color; UV exposure; and family history of skin cancer.26-28 Melanoma is more common in white people than in African American people because of the fair skin risk factor.29 The sun-protective effect of melanin in dark skin likely mediates the lower incidence in African American people. However, the relative risk of melanoma is greater in obese vs nonobese African American men (relative risk, 2.39) compared with the relative risk in obese vs nonobese white men (relative risk, 1.29) according to data from a large cohort of US military veterans.30 Thus, the relative melanoma risk in African American veterans with regard to obesity is similar in magnitude to the risk associated with a family history of melanoma.26,31 Relevant to our study, these results suggest that mechanisms besides sun exposure mediate the increased risk of melanoma in people with obesity.
There are several potential factors that could explain the association among obesity, weight loss, and melanoma.32 For example, the metabolic hormone leptin is upregulated in obesity and is associated with lymph node metastasis in patients with melanoma,33 and melanoma cells, but not melanocytes, express the leptin receptor.34 Obesity leads to chronic systemic inflammation, which could provide a permissive environment for tumor growth.35 In addition, α-melanocyte–stimulating hormone, which is involved in energy homeostasis and skin pigmentation, reduces the expression of adhesion molecules on melanoma cells that normally stimulates immune cell interactions and thereby reduces the ability of the immune system to detect tumor cells.36 Other factors that may be associated with melanoma incidence are changes in lifestyle, such as increased physical activity, or changes in diet after surgery. Obesity is associated with sedentary lifestyle, and prolonged sedentary time has been associated with increased cancer incidence and mortality.37 Bariatric surgery alters gastrointestinal anatomic features and leads to neurologic and physiologic changes associated with hypothalamic signaling, gut hormones, bile acids, and gut microbiota. These changes lead to modifications in eating behavior and food preference, and patients reportedly prefer lower-calorie foods after gastric bypass surgery.38 Further research should focus on distinguishing among the aforementioned factors.
Strengths and Limitations
The strengths of the SOS study include its prospective design, matched control group, long follow-up time, and the possibility of obtaining information from comprehensive national registers. However, the study also has limitations. For example, the high mortality after bariatric surgery in the 1980s made randomization unethical. However, the performed sensitivity analyses (ie, the propensity score–adjusted analysis and the quantification of the possibility of unmeasured confounding) confirm the robustness of the results. In addition, because skin cancer and melanoma incidences were not predefined end points, the study was not specifically designed to address the current research question. A large randomized clinical trial with long-term follow-up that is designed to examine melanoma incidence as a primary end point would be optimal. However, it is questionable whether such a study would be ethical because bariatric surgery is associated with reduced risk of several other serious outcomes, including cardiovascular events and type 2 diabetes.12,14
The global obesity epidemic has been accompanied by increased incidences of many serious diseases, including cancer. These findings suggest that melanoma incidence is significantly reduced in patients with obesity after bariatric surgery and may lead to a better understanding of melanoma and preventable risk factors.
Accepted for Publication: August 26, 2019.
Corresponding Author: Magdalena Taube, PhD, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Vita Stråket 15, S-413 45 Gothenburg, Sweden (email@example.com).
Published Online: October 30, 2019. doi:10.1001/jamadermatol.2019.3240
Author Contributions: Dr Taube had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Taube, Peltonen, Anveden, Carlsson.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Taube.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Peltonen.
Obtained funding: Sjöholm, Carlsson.
Administrative, technical, or material support: Taube, Sjöholm, Andersson-Assarsson, Jacobson, Svensson, Bergo, Carlsson.
Supervision: Taube, Svensson, Carlsson.
Conflict of Interest Disclosures: Dr Bergo reported receiving personal fees from Baxter Medical and LEO Pharma outside the submitted work. Dr Carlsson reported receiving personal fees from AstraZeneca, Johnson & Johnson, and Merck Sharp & Dohme during the conduct of the study. No other disclosures were reported.
Funding/Support: This work was supported by grant R01DK105948 (Dr Carlsson) from the US National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, grant 2017-01707 (Dr Carlsson) from the Swedish Research Council, grants from the Swedish state under the agreement between the Swedish government and the county councils, ALF agreement ALFGBG-717881, and the Swedish Diabetes Foundation.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Additional Contributions: Christina Torefalk and Björn Henning provided administrative support. We thank the Swedish Obese Subjects (SOS) study patients and staff members at 480 primary health care centers and 25 surgical departments in Sweden at which the SOS study was conducted.
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