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Increasing HLA Mismatch May Cut Risk for Skin Cancer (CME/CE)

Action Points

  • Transplant patients with HLA-DR antigen mismatch had lower rates of skin cancer than those with matched HLA types, most notably among those who received lung and heart transplants.
  • Note that patients had a 7%-8% reduction for each HLA mismatch type in skin cancer risk, when researchers controlled for other risk factors, which suggests that chronic exposure to mismatched alloantigens may be responsible for stimulating tumor surveillance mechanisms among solid-organ recipients.

CME Author: Vicki Brower

Study Authors: Yi Gao, Amanda Twigg, et al.

Target Audience and Goal Statement:

Dermatologists, transplant surgeons, immunologists, cardiologists, and pulmonologists

The goal of the study was to retrospectively examine the association between HLA antigen mismatch and skin cancer risk in solid organ transplant patients.

Questions Addressed:

  • What is the association between HLA antigen mismatch and skin cancer (squamous cell cancer, Merkel cell cancer, and melanoma) risk among patients receiving a solid organ (kidney, lung, heart, pancreas, liver) transplant?
  • What might account for the study’s findings?

Study Synopsis and Perspective:

HLA antigen mismatch in heart and lung transplant recipients is associated with a protective effect against skin cancer, according to a secondary analysis of the Transplant Skin Cancer Network (TSCN), according to Sarah Arron, MD, of the University of California San Francisco, and colleagues.

The mismatch effect was not detected for liver, kidney, or pancreas transplant recipients, they wrote in JAMA Dermatology.

TSCN is a multicenter initiative that includes 26 U.S. transplant centers in which dermatology and transplant specialties collaborate.

Effective immunosuppression after a solid organ transplant is a double-edged sword, in that it reduces the risk of graft rejection, but appears to increase the risk of cancer, the authors wrote.

Solid organ transplant patients have an elevated risk of three skin cancers. The original findings from the multi-center TSCN study found that skin cancer occurred at a rate of 1,408 per 100,000 person-years after transplant, with some cancers more common than others:

  • Squamous cell carcinoma: 1,328 per 100,000 person-years
  • Melanoma: 122 per 100,000 person-years
  • Merkel cell carcinoma: 4 per 100,000 person-years

While reducing the number of HLA mismatches typically helps improve graft survival and rejection rates, the group found that mismatches actually reduced the risk of the three skin cancer types, most dramatically, in heart and lung transplant patients. The rate of skin cancer was numerically higher among kidney transplant recipients with no HLA antigen mismatch, but the outcome was not statistically significant (14.5% vs 11.0% in those with one or more HLA mismatch, P=0.13).

In their retrospective cohort study of 10,649 organ transplant recipients, the researchers found a 7% to 8% reduction in skin cancer risk for each additional mismatched allele (adjusted HR 0.93, 95% CI 0.87-0.99, P=0.01).

Conducted from 2016 to 2017, this secondary analysis of the TSCN study included 10,649 patients (6,776 men) with an average age of 51, who received a primary transplant in 2003 or in 2008 to permit 5- and 10-year follow-up. The primary endpoint was time to diagnosis of post-transplant skin cancer, including squamous and Merkel cell cancers, and melanoma.

Thoracic transplant patients had higher levels of HLA mismatch compared with abdominal organ transplant recipients.

With almost 60 000 years of follow-up, the protective effect of HLA antigen mismatch — as defined in the 2016 Organ Procurement and Transplantation Network guidelines — was statistically significant for both lung (adjusted HR 0.70, 95% CI 0.56-0.87, P=0.001) and heart transplant recipients (adjusted HR 0.75, 95% CI 0.60-0.93, P=0.008), traditionally the most immunosuppressed transplant population.

After adjustment for age, sex, race/ethnicity, thoracic organ transplant, year of transplant, and pretransplant history of skin cancer, the reduced risk for developing any skin cancer was statistically significant for HLA-DR mismatch (adjusted HR 0.85, 95% CI 0.74-0.97, P=0.01), but not for HLA-A or HLA-B mismatches.

“The HLA-DR mismatch seemed to play the strongest role,” Arron’s group wrote. “Internists and dermatologists who treat organ transplant recipients should be aware that the risk of skin cancer may be higher in patients who underwent thoracic transplant and received a well-matched organ.”

HLA-DR molecules are most responsible for graft loss in the first 6 months, followed by HLA-B for the first 2 years, and HLA-A is most responsible for long-term graft survival.

HLA mismatching varies widely according to transplanted organ. “In the U.S., no effort is made to match recipients and donors of heart or lung transplants for HLA antigen, but kidney donors are selected to some degree for compatibility at HLA-DR,” explained Michael Cecka, PhD, of the David Geffen School of Medicine at the University of California Los Angeles, who was not involved in the study. “The finding that there is no effect for kidney, but there is for heart and lung is therefore suspicious,” he told MedPage Today.

“These results suggest that chronic exposure to mismatched alloantigens may stimulate tumor surveillance mechanisms in solid-organ transplant recipients that protect against the development of skin cancer,” the authors explained, adding that “tumor surveillance mechanisms may be activated by HLA-antigen mismatch, and well-matched heart and lung transplant recipients may have a higher risk of skin cancer after transplant.”

Source Reference:

JAMA Dermatology, Jan. 23, 2019; DOI:10.001/jamadermatol.2018.4983

Study Highlights: Explanation of Findings

In the U.S., over 140,000 individuals have received a solid organ transplant, and the numbers continue to rise, with transplant rates tripling over the past 25 years. The risk of squamous cell cancer is increased 65-fold, and melanoma is increased three-fold in solid organ transplant recipients, compared with the general population, according to a recent study. Other established risk factors for skin cancer following solid organ transplant included male sex, white race/ethnicity, receipt of a thoracic organ, ages ≥50 at transplant, a long period of immunosuppression, past exposure to a high level of ultraviolet radiation, and a pretransplant history of skin cancer.

In this study, researchers found that HLA-DR mismatch was associated with a reduced risk of skin cancer among heart and lung recipients. While HLA mismatch was associated with reduced skin cancer risk, lung cancer patients actually had higher rates of skin cancer.

The authors explained “A priori subgroup analysis of the association between HLA antigen mismatch and skin cancer risk by organ type determined that the protective effect of standard antigen mismatch was seen among lung cancer [adjusted HR 0.70, 95% CI 0.56-0.87, P=0001] and heart (adjusted HR 0.75, 95% CI 0.60-0.93, P=0.008].”

They did not find an association between recipients of liver, kidney, or pancreas transplant. Among kidney transplant recipients, the overall prevalence of skin cancer was higher among those with 0 antigen mismatch, but this outcome was not statistically significant, they reported. The results were adjusted for other known risk factors, such as age, sex, and pretransplant history of lung cancer.

The authors hypothesized that HLA mismatch protection may stem from the fact that “the allocation and transplant systems put less emphasis on HLA antigen matching for lung and heart allografts than for other organs. In general, heart and lung transplant allografts evoke a stronger immune response, and recipients of these organs receive a higher burden of immunosuppression to prevent rejection. In our cohort, lung transplant recipients had the highest incidence of skin cancer, followed by heart transplant recipients. However, these results show that receiving an allograft with a higher degree of HLA antigen mismatch reduces the risk of skin cancer in heart and lung transplant recipients, the transplant population that is the most immunosuppressed.”

They hypothesized that while high levels of immunosuppression elevated overall risk of skin cancer, potential tumor surveillance mechanisms “that remain intact despite immunosuppression may be more active in protecting heart and lung recipients with a higher level of HLA antigen mismatch.”

“In general, cancers are less common among HLA matched recipients because they get lower cumulative immunosuppression. In this study, I would wonder whether other factors are at work related to the distribution of more common HLA types in certain ethnic groups,” noted Cecka. “For example, HLA matches in random pairings would occur more frequently in patients of Northern European ancestry.”

In the current analysis, the adjusted HRs for squamous cell carcinoma and melanoma were similar to those for any skin cancer; however, due to the smaller number of melanoma diagnoses, the risk did not reach statistical significance.

The authors concluded that follow-up studies should focus on determining how the burden of immunosuppression affects the association between the degree of HLA antigen mismatch and skin cancer risk, as well as the molecular mechanisms that explain the protective effect of HLA antigen mismatch.

Study limitations included selection bias introduced by use of patients from academic transplant centers — compared with all transplant patients in the U.S., a larger proportion of these participants were older, white, and recipients of a thoracic transplant.

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
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