Citrus Fruit and Melanoma: Is There Any Link?

Neil Osterweil

June 30, 2015

Sorry, Florida: people with diets high in citrus fruits, especially grapefruit, may be at modestly increased risk for malignant melanoma, possibly from ingesting photosensitizing compounds found in citrus, findings from a long-term cohort study suggest.

During more than 2 decades of follow-up of more than 100,000 health professionals, individuals who ate citrus fruit 1.6 or more times per day had a 36% higher risk for melanoma than people who stayed off the stuff (less than twice per week), report Abrar A. Quereshi, MD, MPH, from Brown University, in Providence, Rhode Island, and colleagues at Harvard Medical School and School of Public Health in Boston, Massachusetts.

But don't cancel that citrus-tasting tour of the Sunshine State just yet, because the study shows only an association, not causality, and citrus fruits have documented positive effects on other areas of health, cautions a dermatologist in an accompanying editorial.

The study and editorial were published online on June 29 in the Journal of Clinical Oncology.

Photosensitizing Fruit?

"We were interested in this topic predominantly because it's well known that certain fruits and vegetables contain photoactive compounds, and we were interested to see whether consumption of fruits and vegetables rich in these photoactive compounds may be associated with an increased risk for melanoma," Dr Quereshi said in an interview with Medscape Medical News.

The study comes hot on the heels of a different study looking at a possible relationship between melanoma risk in men and the use of drugs for erectile dysfunction, as reported by Medscape Medical News. The authors of that study, however, found no evidence of a causal link between the drugs' mechanism of action and risk for melanoma.

In the current study, Dr Quereshi and colleagues suspected that because citrus fruit and juices are rich in photosensitizing chemicals called psoralens, high intake of citrus products over time could make individuals more susceptible to melanoma than their counterparts who rarely partake of the pleasures of oranges, grapefruits, clementines, lemons, and their ilk.

Psoralens are used to sensitize skin to ultraviolet radiation (UVA) for treatment of skin disorders such as severe psoriasis. But psoralens have also been found in experimental studies to have photocarcinogenic properties, and there is epidemiologic evidence to suggest that long-term exposure to psoralens and UVA phototherapy is a risk factor for malignant melanoma, the authors explain.

"Psoralens had been used as tanning activators until 1996, and individuals who used psoralen tanning activators had a higher risk of melanoma. Psoralen-containing sunscreen users also had a substantially increased risk of melanoma as compared with regular sunscreen users. As a result, strict regulations have been imposed on psoalen-containing suntan lotions and cosmetic products in recent years," they write.

Study Details

To examine this question, Dr Quereshi and colleagues drew on two massive prospective cohort studies, extracting data on 63,810 women enrolled in the Nurses' Health Study from 1984 through 2010 and 41,622 men in the Health Professionals Follow-up Study from 1986 through 2010.

In the entire cohort, there were 1840 incident melanomas during 24 to 26 years of follow-up.

In pooled multivariable analysis controlling for body height and weight, cigarette smoking, physical activity, ingestion of vitamin C from supplements, menopausal status and postmenopausal hormone use among women, family history of melanoma, and personal exposure to known melanoma risk factors, the investigators found a dose-dependent relationship between citrus product consumption and melanoma risk.

Table.

Citrus Consumption Hazard Ratio 95% Confidence Interval
Less than twice weekly (reference) 1.00  
2 - 4 per week 1.10 0.94 - 1.30
5 - 6 per week 1.26 1.08 - 1.47
1 - 1.5 per day 1.27 1.09 - 1.49
≥1.6 day 1.36 1.14 - 1.63 (P < .001)

In a separate analysis of individual citrus products, the strongest association was between consumption of grapefruit halves and melanoma (adjusted hazard ratio [HR] for highest consumers, 1.41; P < .001), with orange juice consumption coming in second (adjusted HR, 1.25; P < .001).

However, consumption of neither grapefruit juice nor whole oranges was associated with increased risk, the authors note.

Study Fails Causality Test

As any fresh-faced medical school graduate will tell you, however, correlation is not causality, and the study, although important, fails to meet all of the criteria for establishing a "smoking-gun" link between citrus intake and melanoma, says a dermatologist who was not involved in the study.

"This is a potentially important study, given that citrus consumption is widely promulgated as an important dietary constituent and has demonstrated benefit for coronary heart disease, cancer prevention, and overall health effects. At this point in time, a public overreaction leading to avoidance of citrus products is to be avoided," writes Marianne Berwick, PhD, MPH, from the University of New Mexico, in Albuquerque, in an accompanying editorial.

Dr Berwick notes that "a number of factors limit enthusiasm for this study." For example, the patients with melanoma had relatively low-risk disease compared with patients in other studies and in the general population, as judged on the basis of a mean Breslow lesion thickness of 0.63 mm, compared with lesions having a mean thickness of 1.28 to 1.49 mm seen elsewhere.

She also points out that risk for melanoma was inconsistent in the analysis by individual citrus type. Additionally, she notes that participants with histories of nonmelanoma skin cancers, who are known to be at high risk for melanoma, were excluded from the study, creating a possible bias, and that continuous but not intermittent UV exposure was associated with melanoma risk, a finding "at odds with the current literature."

This research was supported by the National Cancer Institute. The authors and Dr Berwick report no relevant financial relationships.

J Clin Oncol. Published online June 29, 2015. Abstract, Editorial

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