The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.
Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.
“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.
The case demonstrates just a few of the trade-offs that dermatologists and transplant specialists must make when it comes to preventing and treating cSCC in individuals who receive a solid organ transplant.
Organ transplant recipients have a 200-fold increased incidence of keratinocyte carcinoma compared with immunocompetent individuals, and cSCC accounts for 80% of skin cancers in those recipients, according to a 2022 paper published in Transplant International, by Matthew Bottomley, MRCP, and colleagues at the University of Oxford, England.
And in a 2017 JAMA Dermatology study on skin cancer in organ transplant recipients in the United States, Sarah Arron, MD, and colleagues, wrote that posttransplant cSCC has an incidence of 812 per 100,000 person-years. To put that in perspective, breast cancer has an incidence of 126 per 100,000 person-years and prostate cancer, an incidence of 112 per 100,000 person-years, according to data from the Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Disease Control and Prevention, respectively.
Once a transplant recipient has a single cSCC, he or she is at higher risk for developing multiple lesions and is at greatly increased risk for metastasis and death. Skin cancer-specific mortality in transplants patients is ninefold higher than for immunocompetent patients, reported Johns Hopkins dermatologist Kristin Page Bibee, MD, PhD, and colleagues in a 2020 paper in Oral Oncology.
Clinicians focus primarily on reducing patients’ sun exposure to prevent precancerous and cancerous lesions. While field therapy, such as topical 5-flourouracil, and systemic therapy, including acitretin, can be as effective in treating cSCCs as they are for immunocompetent patients, dermatologists are hoping for more tools.
Dr. Christensen, associate professor of dermatology, Yale University, told this news organization that immune checkpoint inhibitors might become more useful in the future as trials are exploring the feasibility of injecting them directly into the cancers. “That’s a really exciting area of research,” he said, noting that direct injection would lower the risk of transplant rejection.
In an interview, Dr. Bottomley said that he is excited about new techniques, such as high-resolution spatial transcriptomic and proteomic profiling. Those techniques will allow researchers “to identify new pathways and mechanisms that we can target to reduce cSCC risk in both immunocompetent and immunosuppressed patients, ideally without the increased risk of graft rejection that we see with immune checkpoint inhibitors,” said Dr. Bottomley, a consultant nephrologist in the Oxford Kidney and Transplant Unit at Churchill Hospital.
Reducing risk factors
Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.
Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.
The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.
Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.
In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.
Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurringthe development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.
“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”
Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.
Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
When to intervene?
Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.
Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.
A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?
In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
Coordinating with the transplant team
A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.
Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”
Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.
Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.
In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”
Acitretin a go, nicotinamide not so much
Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.
Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.
“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.
Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.
Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.
Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”
Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.
Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”
Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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