Merkel Cell Carcinoma Prognosis Linked to Vitamin D
PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.
A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual caongress of the European Academy of Dermatology and Venereology.
Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.
In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.
The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.
It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.
"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.
Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.
Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.
Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.
"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.
In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.
The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.
Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.
These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).
The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.
Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.
In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.
"For now it’s an interesting curiosity," he commented.
Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.