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Mohs Micrographic Surgery Risks: Carcinogenicity of Immunosuppressive Agents
Introduction
Mohs micrographic surgery is a specialized technique used to treat high-risk cutaneous malignancies, particularly in areas where tissue preservation is crucial for both cosmetic and functional outcomes. Mohs surgeons, who are dermatologists, often collaborate as part of the healthcare care team to address patients with various nondermatologic conditions requiring treatment with immunosuppressive agents. These medications increase the risk of malignancies, making it essential for dermatologic oncologists and Mohs surgeons to understand the carcinogenic potential of these treatments. Many of these medications are prescribed for managing autoimmune diseases and preventing organ transplant rejection.[1]
Many chronic medications suppress the immune system, which can inadvertently impair the body's ability to detect and eliminate cancer cells.[2] Although the exact mechanisms are not fully understood, both direct mutagenic effects and indirect impacts on immune surveillance may weaken the body's defenses against oncogenic viruses. Common immunosuppressive agents relevant to Mohs surgeons include azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, tacrolimus, sirolimus, and tumor necrosis factor-alpha (TNF-α) inhibitors. Although this list is not exhaustive, it highlights key examples where understanding the risks, implementing mitigation strategies (eg, dosage adjustments, patient monitoring, and alternative therapies), and managing adverse effects can help balance carcinogenic risks with the therapeutic benefits of immune suppression.
Function
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Function
Immunosuppressive medications increase the risk of cancer primarily by weakening the body's immune surveillance, which is crucial for detecting and eliminating cancer cells.[3] The immune system is vital in identifying and destroying cancerous cells. Immunosuppressive drugs reduce the activity of immune cells, particularly T cells, which are vital for targeting and eliminating abnormal cells. This reduction in immune function weakens the body's ability to recognize and fight emerging cancer cells.
In addition to a reduced ability to detect malignancies, tumors that do develop in immunosuppressed patients often behave more aggressively.[4] Both the incidence and aggressiveness of these tumors have been linked to the intensity of the immunosuppressive regimen, including the dose and number of medications used concurrently.[5]
Additionally, immunosuppression increases susceptibility to oncogenic viruses, such as Epstein-Barr virus (EBV) and human papillomavirus (HPV), which are known to cause cancer.[6] For example, immunosuppressive use may activate human herpesvirus-8 (HHV-8), which can lead to Kaposi sarcoma. Appropriate workup, including staining for CD31, D2-40, LANA-1, and HHV-8, can confirm the presence of the virus. In such cases, adjusting the dosage may be necessary to reduce the risk of progression or recurrence.
Immunosuppression can reactivate latent infections or make patients more susceptible to new infections, thereby increasing the risk of virus-related cancers. This is especially concerning for patients on long-term immunosuppressive therapy, as persistent viral activity can contribute to oncogenesis.
Moreover, some immunosuppressive medications have direct carcinogenic effects. For example, azathioprine and cyclosporine have been linked to an increased risk of skin cancer due to their mutagenic effects on DNA.[7][8] By understanding these mechanisms, healthcare providers can more effectively monitor and manage the elevated cancer risk in patients taking immunosuppressive medications through regular screening and early intervention strategies.
Issues of Concern
Patients undergoing Mohs micrographic surgery usually have comorbidities and associated treatments that may elevate their risk for malignancy. This risk is typically assessed by comparing the incidence of malignancy in a population taking a specific medication to the background malignancy rate in the general population. This is particularly relevant for conditions like rheumatoid arthritis, which, even when treated with immunosuppressive agents, may already carry a higher baseline risk for malignancy.[9]
Psoriasis has been associated with a mild increase in the risk of solid organ tumors and a moderately increased risk of nonmelanoma skin cancers.[10] Similarly, atopic dermatitis has been linked to a slightly higher risk of lymphoma.[11] Much of the available data to track malignancy risks come from the Surveillance, Epidemiology, and End Results (SEER) database.[12] This comprehensive US-based database has compiled cancer incidence and survival statistics for over 50 years and serves as a key benchmark for measuring background incidence.
With this understanding in mind, several common immunosuppressive medications have been studied through retrospective cohort studies examining the incidence of various malignancies during therapy. Well-powered studies have investigated medications such as TNF-α inhibitors, thiopurines,[13] methotrexate,[14] cyclosporine,[15] tacrolimus,[16] and mycophenolate mofetil.[17] However, the data are not entirely consistent across all findings. While some medications show a clear link to increased malignancy risk, others yield inconclusive results. Additionally, determining the actual attributable risk for each medication is challenging, as patients are often prescribed multiple immunosuppressive agents concurrently to optimize treatment efficacy.
Azathioprine
Azathioprine is a thiopurine immunosuppressive antimetabolite that inhibits purine synthesis, thereby reducing immune cell proliferation and decreasing the body's immune response. Thiopurines, including azathioprine, have been associated with increased risks of lymphoma, nonmelanoma skin cancers, and urinary tract cancers.[18] Pasternak et al conducted a retrospective cohort study involving 45,986 patients with inflammatory bowel disease in Denmark and found that those treated with azathioprine had an increased risk of lymphoma and urinary tract cancer.[19] Similarly, Beaugerie et al examined 19,486 patients with inflammatory bowel disease and demonstrated that those treated with thiopurines had a statistically significant higher risk of lymphoproliferative malignancies.[20]
Cyclosporine
Cyclosporine is an immunosuppressive calcineurin inhibitor that works by binding to cyclophilin, inhibiting calcineurin, and reducing T-lymphocyte activation to suppress the immune response. In addition to impairing the immune system's ability to detect and fight cancer, cyclosporine also has carcinogenic properties through the suppression of PTEN, which leads to subsequent activation of the AKT pathway.[21] Studies have demonstrated a significant increase in squamous cell carcinoma incidence during cyclosporine treatment. In a randomized trial involving 231 posttransplant patients, a comparison of low- and high-dose cyclosporine revealed a dose-dependent increase in the development of squamous cell carcinomas.[22]
A study involving 1252 patients with severe psoriasis treated with cyclosporine across 277 centers in Europe showed a significant increase in squamous cell carcinoma but no statistically significant rise in other forms of cancer.[23] Cyclosporine use has also been linked to an increased incidence of lymphoproliferative disorders, specifically posttransplant lymphoproliferative disorder (PTLD).[24] PTLD is strongly associated with EBV and often regresses when the immunosuppressive regimen is adjusted or discontinued.[25]
Methotrexate
Methotrexate is an immunosuppressive and chemotherapeutic antimetabolite that inhibits dihydrofolate reductase, thereby reducing DNA synthesis and cell proliferation. The association between methotrexate and malignancy remains unclear, as many patients with rheumatoid arthritis, who are often treated with methotrexate, already face a higher risk for lymphoma compared to the general population.[18] The risk of lymphoma associated with methotrexate in patients with psoriasis is negligible when compared to the baseline rates observed in the psoriasis population. However, methotrexate has been shown to increase the risk of nonmelanoma skin cancer in psoriasis patients, regardless of whether they are treated with psoralen and ultraviolet A (PUVA) photochemotherapy.[26] Higher rates of nonmelanoma skin cancers have been observed in patients who received larger cumulative doses of methotrexate.[27][28] However, no significant increase in melanoma incidence has been linked to methotrexate use.[29]
Mycophenolate Mofetil
Mycophenolate mofetil is an immunosuppressive antimetabolite that inhibits inosine monophosphate dehydrogenase, reducing guanine nucleotide synthesis and limiting the proliferation of T- and B lymphocytes. Determining its association with malignancy is challenging due to its less frequent use of mycophenolate mofetil monotherapy, as it is often combined with other agents to reduce the risk of acute organ transplant rejection. A systematic review and meta-analysis found that mycophenolate mofetil was not associated with an increased cancer risk in solid-organ transplant recipients compared to azathioprine use.[30] Furthermore, Molina et al conducted a study of 4098 patients, which showed that mycophenolate mofetil offers mild protective effects against the incidence of squamous cell carcinomas after heart transplant, compared to azathioprine.[17] Independent of azathioprine or tacrolimus use, mycophenolate mofetil has been associated with lower rates of squamous cell carcinoma.[31]
Tacrolimus
Tacrolimus is an immunosuppressive calcineurin inhibitor that binds to FKBP-12, inhibiting calcineurin and reducing T-lymphocyte activity to suppress the immune response. When discussing tacrolimus, it is important to note that the risks associated with oral use differ from those of topical tacrolimus, which is commonly used in dermatology. Topical tacrolimus, primarily prescribed for inflammatory skin conditions such as eczema, varies significantly from oral tacrolimus in terms of systemic exposure and associated risks.
Oral tacrolimus, an immunosuppressant used to prevent organ rejection in transplant patients, has been linked to an increased risk of malignancies due to its systemic immunosuppressive effects.[32] This is significant when counseling patients, as the US Food and Drug Administration (FDA) label for topical tacrolimus carries a black-box warning for malignancies, similar to oral tacrolimus, despite the lack of supporting data for such risks with the topical form.
Patients should be counseled that topical tacrolimus has been consistently shown to be safe and carries no risk of lymphoma or other cancers, as it is minimally absorbed systemically.[16] A systematic review of 21 trials involving 5825 patients using topical tacrolimus found no cases of lymphoma.[33] Similarly, another systematic review of 7954 patients across 314 sites also reported no incidence of lymphoma.[34]
Sirolimus
Sirolimus, an immunosuppressive mTOR inhibitor, binds to FKBP-12 and inhibits the mTOR pathway, thereby reducing T-lymphocyte activation and proliferation. Sirolimus is generally considered to reduce the incidence of malignancy in patients with solid-organ transplants, particularly when compared to tacrolimus. Several well-powered studies have demonstrated a decrease in malignancies with sirolimus use. A 9-year retrospective cohort study by Knoll et al, conducted at 2 academic centers, demonstrated a statistically significant reduction in skin cancer incidence among patients switched to sirolimus for immunosuppression following solid-organ transplantation.[35][36] Additionally, a systematic review and meta-analysis involving 5876 patients across 21 trials demonstrated a significant reduction in malignancy rates with sirolimus used as immunosuppressive therapy.[36]
A large study focusing on kidney transplant patients reported a modest decrease in the incidence of most cancers with sirolimus use, except for prostate cancer. Yanik et al observed a relative increase in prostate cancer incidence, potentially linked to increased screenings.[37] Not all studies support the idea that sirolimus is associated with an overall reduction in malignancies. In a 2023 multicenter analysis, Shaw et al found a slight increase in the risk of malignancy when using immunosuppressive medications after solid organ transplants.[38]
Tumor Necrosis Factor-α Inhibitors
TNF-α inhibitors are immunosuppressive biological agents that bind to TNF-α, preventing it from activating its receptors and reducing inflammation and immune response. This class of medications has an FDA black box warning for lymphoma development, although the data are not definitive. In the treatment of rheumatoid arthritis, a slight increase in nonmelanoma skin cancer was observed with TNF-α inhibitors in a cohort of 46,409 patients from Sweden.[39]
The data on melanoma risk are unclear, with some studies and meta-analyses either unable to rule out an increased risk or showing a slight increase that does not reach statistical significance. A meta-analysis of 7 studies involving 169,399 patients with inflammatory bowel disease or psoriasis found no statistically significant increase in melanoma risk among those taking TNF-α inhibitors.[40] Similarly, a study of 130,315 rheumatoid arthritis patients on TNF-α inhibitors showed no statistically significant increase in melanoma risk.[41]
Clinical Significance
Awareness of the increased incidence of malignancy in a patient population is the first step in improving patient care through targeted prevention and early detection strategies to reduce mortality and morbidity. This approach is crucial as it allows healthcare providers to recognize the elevated risk and prioritize timely interventions. By being aware, healthcare providers can implement targeted prevention strategies, including lifestyle modifications, the consideration of specific medications, and improved early detection through regular screenings and monitoring. These proactive measures can lead to earlier diagnoses, which are often associated with better treatment outcomes, thereby reducing mortality and morbidity. Ultimately, this awareness forms the foundation for a more informed, strategic approach to patient care, improving survival rates and quality of life for the affected population.
Patients on immunosuppressive medications require heightened cancer screening, physician vigilance, and patient education due to their increased risk of developing malignancies. Immunosuppressive drugs weaken the body's immune surveillance, which is essential for identifying and eliminating cancer cells. This reduced immune function necessitates regular and thorough cancer screening for early detection and prompt treatment, ultimately improving patient outcomes and helping to mitigate the elevated cancer risk associated with long-term immunosuppressive therapy.
For patients more vulnerable to all forms of skin cancer, proactive steps should be taken to minimize modifiable risk factors. These measures include reducing UV exposure by using broad-spectrum sunscreens, wearing wide-brimmed hats and long-sleeve clothing, and scheduling regular full-body skin examinations.[42][43] For patients at higher risk of developing lymphoma, patient education should focus on the expected symptoms, such as painless lymphadenopathy, fever, night sweats, weight loss, and fatigue, along with regular follow-ups.
Enhancing Healthcare Team Outcomes
Managing the carcinogenic risks associated with immunosuppressive medications requires an integrated approach that involves a collaborative, interprofessional healthcare team focused on delivering patient-centered care, improving outcomes, ensuring safety, and optimizing team performance. Physicians and pharmacists are central in this coordinated effort, consistently monitoring patients for specific malignancies based on their prescribed medications. Swift identification and treatment of malignancies are crucial, along with the potential use of alternative immunosuppressive strategies. Effective communication among healthcare professionals is essential to ensure prompt diagnosis and treatment, minimize the risk of errors, and foster a well-coordinated response.
The responsibilities within the healthcare team should be clearly defined. Physicians are responsible for diagnosing conditions, initiating treatment, and monitoring patients for adverse effects. Pharmacists are crucial in ensuring the appropriate selection and administration of medications. Collaborative decision-making with patients is essential to provide guidance, secure informed consent, respect patient autonomy, and uphold the principles of beneficence and nonmaleficence.
Patient preferences are central to this shared decision-making process, which involves discussing the inherent tradeoffs of immunosuppressive therapies. Ongoing education and training keep the healthcare team informed about best practices and the statistical risks associated with malignancies. A patient-centered approach ensures that the patient’s well-being and values are prioritized in every decision. By assessing and managing the carcinogenic risks of immunosuppressive medications, the interprofessional healthcare team delivers comprehensive care, minimizes complications, and emphasizes patient safety and quality outcomes.
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