By Diane Donofrio Angelucci, contributing writer, September 01, 2014
Organ transplant recipients often gain a new lease on life after surgery, but they can face numerous challenges — including an increased risk of skin cancer.
“From a dermatology perspective, skin cancer and particularly squamous cell carcinoma (SCC) are increased 65 to 100 times in solid organ transplant recipients,” said Sarah Tuttleton Arron, MD, PhD, associate director of the University of California, San Francisco (UCSF), Dermatologic Surgery and Laser Center. “As people are living longer after transplants, they’re starting to develop late post-transplant complications, including skin cancer. What we’ve learned over the past 10 to 15 years is that patients who are at incredibly high risk for skin cancer can be aggressively and carefully managed after transplant so that we can reduce this risk.”
The AAD’s Cutaneous Oncology Workgroup is investigating the incidence of SCC after transplantation through the Transplant Skin Cancer Network, said Dr. Arron, who is leading the network’s effort at UCSF. This is a multi-center, collaborative effort to create a stronger network for research needed to help improve the care of patients. “I’m working very closely with transplant dermatologists and transplant physicians at a number of universities to identify what questions are important for us to learn more about and whom can we rally to work on these questions,” she said.
“We’ve done about 600,000 transplants now to date, and there are probably a little over 250,000 living transplant recipients in the United States right now. So there are a lot of people at risk in terms of the development of skin cancer, and their risk is significant,” said Thomas Stasko, MD, professor and chair in the department of dermatology at the University of Oklahoma Health Sciences Center.
“Dermatologists need to remember that the approach to skin cancer in transplant recipients follows the general principles, but that we need to have an increased awareness of the high risk for multiple primaries, the high risk for recurrence, the high risk for metastasis, and the high risk for death in this population,” Dr. Arron said.
Therefore, more frequent skin cancer checks may be necessary, or dermatologists may need a lower threshold to biopsy suspicious lesions instead of attempting to treat them with superficial treatment without a biopsy diagnosis, Dr. Arron said. Dermatologists must also be alert to the potential for lymph node metastasis, potentially performing imaging more frequently and erring on the side of more thorough treatment of skin cancers to reduce that risk of spread, she said.
Increased risks have been attributed to the immunosuppression from medications patients must take after transplantation to prevent rejection. Furthermore, these immunosuppressive agents may be carcinogenic to skin cells, increase sun sensitivity and the risk of skin cancer, or induce proliferative mechanisms that may perpetuate skin cancer, Dr. Stasko said.
“The length of time that people have been immunosuppressed as well as their doses increase their risk,” said Chrysalyne Schmults, MD, MSCE, assistant professor of dermatology at Harvard Medical School and director of dermatologic surgery at Brigham and Women’s and Dana Farber Cancer Center in Boston. Therefore, patients taking higher doses or treated for a longer period are at higher risk.[pagebreak]
The first strategy for addressing increased skin cancer risk in transplant patients is prevention. Therefore, dermatologists must engage patients in this effort.
“One of the things that transplant patients need to be aware of is how even small doses of sun exposure can increase their rate of developing skin cancers, so they might need to be more strict than the immunocompetent population,” said Christopher Miller, MD, director of dermatologic surgery at the Hospital of the University of Pennsylvania.
“I always tell all of my patients that they should never get another burn or tan — that they should maintain their natural skin color all year round and they need to do whatever sun-protective behaviors they need to do to achieve that,” Dr. Schmults said.
Dr. Arron provides patients with an instructional booklet and directs them to a website describing their risks, the appearance of skin cancers, and how to prevent them through scrupulous protection of their skin with sunscreen, sun-protective clothing, and other measures. Furthermore, she reinforces this information during each visit.
In addition, dermatologists should remind patients to examine their skin regularly and explain how to perform a thorough examination. When patients have a new or changing lesion, they should seek treatment before it becomes a problem, Dr. Miller said. Furthermore, patients of color need to know how skin cancer can present in darker skin types because dermatologists might not follow them as closely, Dr. Schmults said.
When transplant patients detect a suspect lesion, they need to know what to do next, particularly if they have multiple lesions, Dr. Stasko said. “They can’t necessarily wait for six or eight weeks when they see something that’s growing rapidly,” he said. “So we need to provide them with instructions on how to contact us easily, and we need to make sure that our staff members know that they need to be seen perhaps more quickly than the average patient and assure that they receive a timely appointment."
Increased surveillance is also key. “If somebody has evidence of actinic damage, actinic keratoses, or if they have a prior history of a skin cancer, then you’re going to want to follow these patients closely, perhaps even with every three- to four-month skin exams, depending on the severity of the way their skin looks now and how many skin cancers they’ve had in the past,” Dr. Schmults said.
Furthermore, dermatologists need to effectively remove cancers and prevent new lesions. “These patients do develop a lot of superficial cancers that can be cured just by destructive methods like electrodessication and curettage, but many of them do require excision to cure them,” Dr. Miller said. However, many patients have field disease, with numerous lesions covering their skin, and will need field therapy, he said.
Field treatments include photodynamic therapy, topical 5-fluoruracil, and chemo wraps, where topical 5-fluorouracil is used under occlusion. “Those treatments are very, very helpful for bringing diffuse actinic damage under control, and that can also really help to clarify your physical exam,” Dr. Schmults said.
“If people develop any high-stage tumors, they may benefit from specialty consultation with a skin cancer group that manages aggressive tumors and has a multidisciplinary team,” Dr. Schmults said.
“If a tumor is invading bone, for example, a dermatologist won’t be able to remove that tumor completely in the office,” Dr. Miller said. “However, we often work with a multidisciplinary team where we can help make sure that the approach to the cancer removal is as effective as possible in making sure that the microscopic margins are clear.”
Dr. Arron explained that there have been excellent publications on staging SCC, an updated staging system from the American Joint Committee on Cancer and a new staging system from Brigham and Women’s Hospital (www.nccn.org, www.cancerstaging.org, J Clin Oncol. 2014;32:327-334). “What I do is evaluate the potential high-risk features in that tumor,” she said. “Was it greater than 2 cm? Was there perineural invasion? Is the tumor on a high-risk location like the ear or the lip? Based on that information, I will triage the patient for surgery. The vast majority of patients will have a surgical excision and not require any further workup.”
Nodal staging in high-risk SCC is performed primarily by imaging but sometimes by sentinel node biopsy. If the patient has a palpable lymph node, fine-needle aspiration is performed, Dr. Arron said.
“The primary advice I have for general dermatologists is that if they are considering two treatments in a transplant recipient, I would counsel them to err on the side of the more definitive or more complete treatment,” Dr. Arron said. “This can be challenging in patients who have hundreds of skin cancers because they do develop treatment fatigue. Unfortunately, in my referral practice, I have to handle complications of metastatic SCC that was undertreated at its primary presentation. The first presentation of the tumor is our best opportunity for cure.”[pagebreak]
Dermatologists need to keep the channels of communication open with the transplant team when treating organ recipients, consulting them regarding disease progression and potential treatments.
“The transplant physicians basically take the primary care of these patients and maintain their immunosuppressive medications,” Dr. Stasko said. “Because some of the therapies that we would like to do might have implications with regard to their transplanted organ or implications with regard to their immunosuppression, it’s important to develop a great working relationship with your transplant doctors.”
In some cases, the transplant team, whose main goal is to protect and preserve the organ and the patient’s general health, may consider immunosuppressant side effects a secondary outcome and overlook them, Dr. Miller said. “The dermatologist can play a role in advocating and communicating with the transplant team when somebody is in trouble because their skin is not controlled,” he said.
Dermatologists are an indispensable resource to the transplant team. “The vast majority of work in skin cancer incidence and outcomes in transplant patients has been done by dermatologists, and it has been published in dermatology journals, so dermatologists really are the people who are the repositories of that knowledge base about how to manage these patients,” Dr. Schmults said.
The transplant team needs to know if multiple dermally invasive squamous cell cancers are developing, particularly high-stage tumors. “In those cases, sometimes the transplant team will elect to decrease the patient’s immunosuppression based on how safe they think that is for the grafted organ, how severe the skin cancer formation is, and how much of a mortality risk they think that’s posing to the patient,” Dr. Schmults said.
Patients may also be switched to sirolimus or another mTOR inhibitor, Dr. Schmults said.
A study published in the New England Journal of Medicine in 2012 demonstrated that kidney transplant recipients switched from calcineurin inhibitors to sirolimus had fewer SCCs and it took longer for the next lesion to develop (26;367:329-339). However, this study only considered secondary prevention after SCC had developed.
Dr. Arron explained that dermatologists may alert the transplant team to these data.
Chemoprophylaxis with acitretin may help reduce SCC after transplant, Dr. Arron said. “It has no effect on the immune system and no effect on immunosuppression, and it is compatible with all of the immunosuppressant agents that I’ve worked with,” she explained. However, she said, dermatologists should not begin this treatment without working with the transplant service to monitor lab tests and medication interactions.[pagebreak]
Transplant teams must report transplant malignancies to the United Network for Organ Sharing Database, but cases are typically underreported, Dr. Arron said. Therefore, she encouraged dermatologists to send the pathology reports for all post-transplant skin cancers to the transplant team so they can be reported.
In addition, resources such as the International Transplant Skin Cancer Collaborative (ITSCC) are available, Dr. Arron said. Website resources include a bibliography to alert dermatologists to new findings and a listserv, where members can obtain advice on cases.
The Transplant Skin Cancer Network also will provide information to guide dermatologists caring for these patients. Dr. Arron invites dermatologists who would like to participate to contact her through the Transplant Skin Cancer Network (email Reva Bhushan at email@example.com for more information). “My goal is that our research is going to identify mechanisms for improving clinical care that will then be disseminated though the AAD,” she said.
Furthermore, ITSCC also developed a train-the-trainer slide presentation, the AT-RISC Slide Set, which is available free of charge to any dermatologist. “It includes teaching slides that they can use in any way they like and modify as they see fit. It is designed to teach transplant physicians, transplant nurses, and transplant patients about the risks for skin cancer,” Dr. Arron said. “What we hope general dermatologists can do is really be nodes for additional teaching out into the community.”
Editor’s Note: Dr. Arron is the principal investigator for the Transplant Skin Cancer Network. Dr. Stasko, Dr. Schmults, and Dr. Miller have no financial interest related to their comments.