Amid a boom in organ donation, a heightened focus on cancer risk in transplant recipients

Abstract

In 2023, the United States set a record for organ transplants, with more than 46,00 transplants performed with organs procured from more than 16,000 deceased donors and nearly 7000 living ones.¹ With this encouraging trend reported by the Organ Procurement and Transplantation Network (OPTN), though, experts have stressed that the lifesaving operations can carry a tradeoff. Although it has happened only rarely, some donors’ metabolic disorders or nascent tumors have evaded detection before the transplant, the latter resulting in the documented transmission of glioblastoma multiforme and lung, breast, colorectal, kidney, and other cancers.

More commonly, donors can transmit parasitic, fungal, bacterial, or viral infections, including some cancer-linked pathogens such as Helicobacter pylori, hepatitis B, and hepatitis C, as well as more ubiquitous viruses such as Epstein–Barr virus and human papillomavirus (HPV). H. pylori has been linked to gastric cancer, chronic hepatitis, and liver cancer; Epstein–Barr to non-Hodgkin lymphoma; and HPV to cervical, anal, penile, and oropharyngeal cancers.

A 2021 study by OPTN’s Disease Transmission Advisory Committee (DTAC) suggested that donor-derived disease transmission occurs in less than 1% of all transplant recipients. Of the proven or probable donor transmission events, 67% involved infections, 29% included malignancies, and 6% involved other disease processes (a small percentage involved more than one kind of event).²

Gerald Berry, MD, a professor of surgical pathology at Stanford University in Palo Alto, California, and a cancer expert on the DTAC, says that the committee first tries to determine whether a transmissible event is donor-derived or originates in the recipient. “Then the subcategory is, even if it’s donor derived, was it there at the time of transplant and too small to actually detect?”

The DTAC’s work toward determining whether a malignancy can be traced back to the donor, even years after the fact, can help to establish the risk for the remaining cohort of transplant recipients. “Many times, the donor is providing organs for more than one recipient, so the biggest concern is when a recipient develops a malignancy, are the other recipients at risk?” Dr Berry says. The risk can be further characterized according to tumor type: A donor’s brain tumor that has metastasized, for example, would pose a considerably bigger danger than a far more treatable thyroid tumor.

The most significant cancer-related risk for organ transplant recipients, however, is associated with the very immunosuppressive medications that are required to prevent rejection of the organs but also can render the immune system less able to identify and kill tumor cells or battle cancer-linked infections. “The patients are so heavily immunosuppressed as part of the transplant protocol that the host versus the virus mechanisms are distorted, so things like that can then proliferate,” says Dr Berry.

Compared to the general population, transplant recipients face a 2- to 4-fold higher risk for multiple cancer types. A 30-year cohort study in Finland that examined roughly 6500 transplant recipients, for example, found that nearly 1 in 4 eventually contracted cancer; this translated to a 3.6-fold higher risk.³

For non-melanoma skin cancers, such as basal cell and squamous cell carcinomas, the rate is even higher: Studies have documented anywhere from a 25- to 250-fold increase in risk.⁴ Although most of these cancers are relatively benign, transplant recipients also develop more locally advanced or advanced stage cutaneous malignancies, says Kevin Emerick, MD, director of the Division of Head and Neck Cancer Surgery at Massachusetts Eye and Ear in Boston.

“As we do more and more transplants, we’re going to have more and more of those patients,” says Dr Emerick, who also serves as codirector of the clinic’s Non-Melanoma Skin Cancer Multidisciplinary Clinic and Program. “So maybe a good trend is a recognition and acknowledgment of the special care that those patients need.” With more patients living longer after transplantation, more will require long-term follow-up. At many academic medical centers, he points out that dermatology departments are creating high-risk clinics that specifically cater to the growing number of solid organ transplant patients, some of whom need to be seen every 6 or 12 weeks.

According to one Italian study of more than 1300 heart or kidney transplant patients, “the overall risk of developing skin cancer increased from a cumulative incidence of 5.8% after 5 post-transplant years to an incidence of 10.8% after 10 years of graft survival.”⁵ Studies from other countries have documented even higher rates.

One take-home message, Dr Emerick says, is the need for dedicated providers to conduct routine surveillance and for sufficient infrastructure and teams to care for those patients who develop skin cancer. Even more than the risk for other cancers, the risk for skin cancer is based overwhelmingly on recipients’ immunosuppression and the ability of cancerous lesions to evade immune surveillance. “Our immune system just plays such a critical role in helping to suppress and clean up DNA damage, and we all have a ton of DNA damage in our skin,” Dr Emerick says. “So, if you take away that surveillance effect of our immune system, this is why patients are getting a lot more skin cancers.”

Consequently, the cancer risk associated with a new liver may be high in comparison to the risk for the general public, but the risk is even greater with a new heart. Similarly, small bowel and lung transplant patients tend to have a higher incidence of post-transplant lymphoproliferative disorder, a life-threatening type of lymphoma also seen after hematopoietic stem cell transplantation in which white blood cells multiply uncontrollably.

Patients living with a transplanted kidney for years or decades may be able to decrease their immunosuppression regimen, and older patients generally have less active immune systems; conversely, living longer with a transplanted organ can increase the risk over time.

For some patients, switching immunosuppressants (e.g., from tacrolimus to sirolimus) may reduce the risk of developing skin cancer. “This is where partnering with people’s transplant teams is so important,” Dr Emerick says. “They’re the real experts at finding the right level of immunosuppression that [transplant recipients] need to maintain their organ, which is so important for these folks, especially our heart and lung transplant patients.”

Risk-reduction strategies, such as vaccinating patients against hepatitis B and HPV and prioritizing prevention messages (e.g., emphasizing the importance of avoiding more ultraviolet radiation from sun exposure), could benefit patients even when they are on an organ transplant wait list. Patients with more skin pigmentation have a lower risk of developing both non-melanoma and melanoma skin cancers, including after organ transplantation, because of the protective role of melanin against cumulative exposure to ultraviolet radiation. Even so, Dr Emerick says, their risk for other cancers remains elevated, and constant vigilance is required.

One cruel irony of advanced skin cancers that develop after organ transplantation is that immunotherapy is a key anticancer treatment. “Skin cancers are the most treatable cancer by immunotherapy,” Dr Emerick says. “Unfortunately, immunotherapy comes with a significant risk of losing your transplanted organ.” Anticancer immunotherapy can be used for some renal transplant patients, he says, “largely because if their organ fails, you do have an option to consider dialysis.” That same option is not available to lung, heart, and most liver transplant patients because losing the organ would kill them.

The fact that immunosuppression helps to prevent the rejection of a donated organ but raises the risk of a host of other diseases reinforces the crucial importance of long-term cancer surveillance and early detection for transplant patients, says Dr Emerick and other experts. So does the possibility that a transmitted malignancy may not present itself clinically until years after the transplant, Dr Berry adds. “It’s not only looking at the survival risk or morbidity-mortality risk to the poor recipient who is unfortunately the one who has developed the tumor, but then we also look at risk stratification for the remainder,” he says.

Fortunately, most such patients are seen at regular intervals after transplantation, and these visits provide ample—and crucial—opportunities for screening and risk evaluation.