Older male patients who have undergone heart transplant are at a higher risk for developing squamous cell carcinoma post-surgery. In addition, certain immunosuppression agents can increase the risk of basal cell carcinoma. Researchers from the Mayo Clinic in Rochester, Minn., and the Yale School of Medicine in New Haven, Conn., conducted a study to hone in on the factors that contribute to skin cancer after heart transplant.

Jerry D. Brewer, MD, Clark C. Otley, MD, and colleagues retrospectively reviewed medical charts for 312 heart transplant recipients at the Mayo Clinic (see Table). Of these patients, only one died of malignant melanoma, a little over eight years after transplant. For the remaining patients, a total of 1,395 skin cancers developed, with the majority (89%) being squamous cell carcinoma (SCC). Seventy-six patients (24.4%) had at least one SCC. The largest number of post-transplant SCCs in a single patient was 306 in 8.4 years. Overall, 46.4% of the patients had skin cancer by 19 years of follow up, the authors reported (Arch Dermatol 145:1391-1396, 2009).

Their evaluation of basal cell carcinoma (BCC) tumor burden found that 54 heart graft patients (17.3%) had at least one BCC. The largest number of BCCs that developed in an individual patient was 17 in 8.4 years. The authors determined that the cumulative incidence rates of a second BCC increased at a rate of 32.1% at one year, 48.6% at three years, and 51.4% at five years.

The most significant risk factors for the development of SCC were increased age at transplant (10-year hazard ratio [HR] 2.57; P < .001), presence of herpes simplex virus infection (HR 2.71; P = .02), and post-transplant non-skin cancer (HR 2.32; P = .001). Also, ischemic cardiomyopathy vs other causes of heart failure led to an increased risk of SCC (HR 0.07; P = .01). However medications such as azathioprine, cyclosporine, mycophenolate mofetil (CellCept), and sirolimus were not significantly associated with SCC development.

The authors also reported that male sex was associated with increased risk of SCC after heart graft . When taken together with increased aged, "these characteristics are both most likely markers of increased UV exposure, compared with female sex and younger age."

A dietary connection

The link between SCC and ischemic cardiomyopathy may be dietary, the group wrote. "It has been suggested that a high-fat diet may increase the incidence of actinic keratosis...perhaps the influence of high-fat diets leading to ischemic cardiomyopathy, in combination with the immunosuppression of heart transplant, is what places this group of patients at greater risk."

The most significant risk factors for the development of BCC were older age at transplant (HR 1.77; P < .001), posttransplant infection with herpes simplex virus (HR 3.55; P = .008), and mycophenolate mofetil use (HR 2.32; P = .005). The authors noted that use of azathioprine was associated with a decreased risk of BCC (HR 0.56; P < .05).

The authors acknowledged the limitations of their study, including the retrospective analysis of single-institution data. But they emphasized two important take-home messages. First, heart transplant patients should be encouraged to use sun protection, have regular skin examinations, and supplement their diets with vitamin D. Second, the number of non-melanoma skin cancers (NMSC) per year after transplant held steady in this population.

"When assessing the mean number of SCCs per year...we found that the mean did not change considerably in the early years of transplant compared with more than a decade later," the authors wrote. "The present student suggests that with aggressive screening and treatment of [NMSC], the mortality rate associated with NMSC can be substantially decreased."

Vantage Point
Results refine which patients require close follow up

The study authors took on a difficult question by looking at NMSC in a patient population in which the incidence of melanoma is higher, said Dr. Cranmer, an assistant professor of clinical medicine at the Arizona Cancer Center, University of Arizona in Tucson.

"Certainly the number of people on immunosuppressants is growing and we have thought that these patients are at higher risk of skin cancer. This study offers confirmatory data that helps us focus on how these patients should be managed with close dermatological surveillance," Dr. Cranmer said. "Do I think all of these patients require more than annual dermatological surveillance? No, I don't. This study identifies some subsets of transplant patients for more aggressive dermatologic follow-up, such as those with post-transplant non-skin cancer, herpes simplex infection or non-melanoma skin cancer."

Dr. Cranmer said that he was particularly intrigued by the fact that in this study population, only one patient died of skin cancer, specifically from melanoma. "In my practice, I have a number of transplant patients who've had non-melanoma skin cancer and have died of it, although that is very rare. It raises the issue of how to treat these patients with aggressive nonmelanoma skin cancer if surgical or local therapy doesn't work. What is the next treatment option? That is still undefined, even in non-transplant patients, let alone in those with medical immunosuppression."

"I would be interested to see if these results could be generalized to all patients who are taking immunosuppressants," he said. "I think it's certainly an issue that the Mayo Clinic has the data and resources to look into."