Transplant Patients at High Risk for Melanoma: Increased Monitoring Necessary

Journal of Investigative Dermatologyhas helped to confirm the correlation between transplantation and increased risk of melanoma.^1-3

In 1971, cancer treatment pioneer Henry S. Kaplan, MD, published a paper entitled “The Role of Immunologic Disturbance in Human Oncogenesis: Some Facts and Fancy.” Amongst other topics, he reviewed evidence that immunosuppressives used in transplantation medicine, such as azathioprine and antilymphocyte globulins, may induce malignancy.⁴

In the study published in theJournal of Investigative Dermatology,Hilary A. Robbins, MSPH, a PhD student in the Department of Epidemiology at the Bloomberg School of Public Health, Baltimore, Maryland, et al sought to define transplant-related risk factors and quantify the impact of transplantation on melanoma survival, using a large population of US transplant recipients.³

“We knew that melanoma was more likely [to occur] in transplant recipients, but we thought it might be a function of intensive screening, since they are very likely to develop less deadly forms of skin cancer and are checked regularly by dermatologists,” said Robbins in a press release.^3,5

The study authors noted that other explanations have also been hypothesized.⁴In fact, there are reports that the immunosuppressants themselves (eg, cyclosporine) may be carcinogenic.^3,6,7

Recent advances with immune checkpoint inhibitors have demonstrated the importance of immune response, and the study authors proposed that melanoma could exhibit a more aggressive phenotype when the immune system is impaired.^3,8

“We were surprised to see that transplant recipients were particularly at risk for developing melanomas that weren’t found until they had already spread,” said Robbins.⁵The study found that transplant recipients were twice as likely to develop melanoma and three times more likely to die of melanoma than nontransplant recipients.^3,5

Transplant Cancer Match Population

The team used data from the Transplant Cancer Match study,²which linked the Scientific Registry of Transplant Recipients (SRTR), which captures all data on US transplants, with 15 population-based cancer registries. For melanoma incidence, the analyzed cohort included 46.5% of all US transplant recipients between 1987 through 2010 versus the general population.

Associated risk factors were identified using multivariable Poisson models. Non-Hispanic whites were selected because of the very low incidence of invasive melanoma in other groups. First diagnosis of melanoma was used for the incidence analysis, and repeat transplants were considered separately. In a second analysis, which examined a different data set, the researchers compared survival after invasive melanoma in transplant recipients versus nonrecipients.³

Incidence of Melanoma: Demographics

The study analyzed the incidence of melanoma in 139,991 non-Hispanic white transplant recipients versus the general population. The median follow-up time was 4.0 years, and the majority of recipients were male, with a kidney transplant (62.9%; 50.5%).

The researchers found invasive melanoma in 519 recipients and calculated that the risk of developing invasive melanoma was more than double the general population (standardized incidence ratio [SIR] = 2.20, 95% CI, 2.01-2.39). Increased risk was evident across all tumor stages but highest for regional-stage melanoma (SIR = 4.11, 95% CI, 2.85-3.90), and a modest increase for in situ melanoma (SIR = 1.47, 95% CI, 1.27-1.69) versus the general population.³

Factors associated with higher risk from the multivariable models for localized and regional/distant melanoma are given in the table.³

Table: Factors Associated With Higher Risk in Regional and Distant Melanoma

Localized Melanoma

Regional/Distant Melanoma

Male sex

Male sex

Increasing age

Increasing age

Azathioprine maintenance therapy

Polyclonal antibody induction therapy

No significant variance was found in the incidence of localized melanoma with time from transplant, although the study did identify higher incidences at some later time points. In contrast, the incidence of regional-/distant-stage melanoma rose quickly during the initial 4 years post-transplant, but then declined (possibly reflecting the more intense immunosuppression administered in the early post-transplant phase).³

According to the press release, early-stage melanomas were more likely to be found in recipients who were administered a medication called azathioprine, a maintenance drug given long term to some transplant recipients. The press release also noted that this drug is known to multiply the effects of ultraviolet radiation, which could lead to the development of melanoma; late-stage cases of melanoma were associated with use of medication [polyclonal antibody induction therapy] given at the time of transplant that stops T cells from functioning, in order to keep them from attacking the new organ.^5,9

Invasive Melanoma: Survival After Diagnosis

Using a different population, the team analyzed 131,540 patients diagnosed with invasive melanoma, and 182 of these were transplant recipients. Upon follow-up, researchers found that 50 (27%) transplant recipients versus 16,380 (12%) nontransplant recipients, had died due to the melanoma. The transplant recipients had a 3-fold greater mortality from melanoma than nontransplant recipients (HR, 2.98, 95% CI, 2.26-3.93).³

Transplant Recipients: Implications for Management

The findings suggest that transplant candidates should be screened carefully for skin cancers before receiving transplant, according to Robbins, and also that some melanomas may be present at the time of transplant and immunosuppressive drugs may contribute to the spread of the malignancy. She also said that closer monitoring after transplant may allow for earlier detection and possibly prevent patients from developing deadly metastatic cancer.⁵

Fortunately, Robbins commented that many researchers are developing transplant protocols to reduce or even eliminate the need for lifelong immunosuppressive medications, because, in addition to adding to the risk of malignancy, these agents may also contribute to other medical problems.⁵

References:

1. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4:905-913.

2. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306:1891-1901.

3. Robbins HA, Clarke CA, Arron ST, et al. Melanoma Risk and Survival Among Organ Transplant Recipients. J Invest Dermatol. 2015 Aug 13. doi: 10.1038/jid.2015.312.

4. Kaplan HS. Role of immunologic disturbance in human oncogenesis: some facts and fancies. Br J Cancer. 1971;25:620-634.

5. Newswise. Transplant recipients more likely to develop aggressive melanoma http://www.newswise.com/articles/view/638598/?sc=sphr&xy=10013055. Accessed August 20, 2015.

6. Han W, Soltani K, Ming M, et al. Deregulation of XPC and CypA by cyclosporine A: an immunosuppression-independent mechanism of skin carcinogenesis. Cancer Prev Res (Phila). 2012;5:1155-1162.

7. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530-534.

8. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133