Organ transplant is the only way to extend the lives of many patients with end-stage organ failure. This procedure is not without the associated risks involved since the time of its inception. Cancer is one of the three major causes of death after an organ transplant. Cardiovascular disease and infection are the other two reasons for death after an organ transplant, but they both are decreasing in frequency because of effective screening, prophylaxis, and interventional therapies. Understanding of post-transplant malignancy is inadequate regarding early detection and lack of established guidelines. The risk factor is most elusive because of altered dynamics of immunity, host response, and different clinical presentation. Studies have shown an overall two to four-fold elevated risk of cancer after the organ transplant. The mechanisms involved in the oncogenesis are long-term immunosuppression leading to reduced immune surveillance of neoplastic cells, and the opportunistic post-transplant infections especially viral infections because of Epstein-Barr virus (EBV), Varicella, Cytomegalovirus (CMV), and Human herpesvirus (HHV)-8, etc. Physicians and patients face a challenging problem that cancer after an organ transplant is more biologically aggressive and patients may receive less aggressive cancer treatment because of comorbidities and the fear of transplant rejection. In this article, we will discuss the epidemiology, pathophysiology, presentation, diagnosis, screening and treatment strategy for cancer after organ transplantation.
The risk factors for post-transplant malignancy are the patient, transplant, and medication-related.
Patient-related Risk Factors
The advanced age of the patient is a well-described risk factor, and it is an established risk factor for the development of skin cancer. Sun exposure, prior history of cancer in a transplant recipient are also strong risk factors. Acuna et al. in their meta-analysis showed that pre-transplant malignancy correlates with an increased risk of cancer-specific mortality and of developing de novo malignancies after transplantation, compared with solid organ transplant recipients without a pretransplant malignancy. Smoking and alcohol consumption are risk factors for carcinogenesis and carry a high risk of mortality. Viruses implicated in carcinogenesis include Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), human papillomavirus (HPV), the Merkel cell polyomavirus, hepatitis B, and hepatitis C. EBV is implicated in the development of Hodgkin disease, Non-Hodgkin lymphoma, and other manifestations of PTLD, nasopharyngeal cancers and leiomyosarcomas.
Transplant-related Risk Factors
Differences in the type of transplant (living versus deceased) correlate with cancer risk. Patients who receive kidneys from a living donor have a lower risk for genitourinary cancer and PTLD. Donor transmission as a cause of post-transplant malignancy is a rare but is a documented way of carcinogenesis; melanoma, cancer of lung, breast, colon, rectum, kidney, Kaposi sarcoma, and glioblastoma multiforme all have been reported to be transmittable from donors.
Medication-related Risk Factors
The immunosuppressive drugs impair immunosurveillance of neoplastic cells and increase the incidence of virally induced malignancies. The type, intensity, and duration of immunosuppressive therapy all influence the rate of carcinogenesis. These immunosuppressive drugs, for example, biologic agents (anti-thymocyte globulin, basiliximab), corticosteroids, antimetabolites (azathioprine, mycophenolate mofetil), calcineurin inhibitors (cyclosporine, tacrolimus), and mTOR inhibitors (rapamycin [sirolimus], everolimus) all have been implicated.
The Israel Penn International Transplant Tumor Registry (IPITTR), the largest and most comprehensive registry in the world records non-melanoma skin cancers (NMSCs) as the most prevalent cancer in post organ transplant state. Following is the list of various cancers associated with the organ transplant:
Other common malignancies with a statistically significant (p<0.001) increase included
Transplant-related malignancies arise from an interplay of immunologic and nonimmunologic risk factors. The following is a brief description of the various pathways for the oncogenesis:
Although early cancer diagnosis may show improvement of cancer outcomes in the cancer population, the reduced life expectancy and multiple comorbidities that exist in organ transplant recipients regular physical examination and history are of paramount importance. On average, the age at diagnosis of post-transplant cancer is 40 years and the time from transplantation is the 3 to 5 years. However, these numbers vary according to the cancer subtype, with lymphoma and Kaposi sarcoma occurring early after transplantation and epithelial cancers later on. The specific questions on history taking that are of paramount importance are the amount of high sun exposure, any skin health concerns, and the onset of irregular skin lesions, as they all point towards the onset of skin malignancy. Studies have shown that continued consumption of alcohol and smoking lead to early and aggressive squamous cell malignancy and urinary bladder cancer. If there is a concern for fever, weight loss or any neurological disturbance, then radiological investigations should be performed to rule out PTLD. If the patient endorses lower GI bleed, then threshold to examine colon to rule out malignancy should be low. The history taking in patients with solid organ transplant is more vigorous and frequent than the general population. Physical examination should be carried out keeping in mind all the secondary cancers that may arise. Regular skin and breast examination should be performed in the office, a digital rectal exam to detect early prostate cancer, and neurological examination to clinically rule out CNS lymphoma and PTLD.
Screening and early detection of cancers is the best form of treatment. Below are the recommendations for the screening of the specific malignancy.
Careful screening of the patient and donor before transplantation to help detect an underlying pre-existing malignancy is one of the effective ways to avoid dealing with this enigmatic problem later on. We have tried to summarize the broad topic of management and cancer in solid organ recipients into general recommendations;
Reduction of immunosuppression: Reduction or cessation of immunosuppressive therapy is useful primarily in patients who had a renal transplant since the loss of the graft to rejection is not a fatal event in these patients. Such measures may cause tumor regression sometimes such as PTLD, some skin cancers, Kaposi sarcoma (KS). The reduction in calcineurin inhibitor exposure may be important.
Anogenital cancers: In situ anogenital cancers can be treated with laser therapy, electrocautery, or topical fluorouracil. Invasive tumors require wide local excision (e.g., APR), with inguinal lymphadenectomy.
Visceral malignancy: Visceral malignancies are to receive treatment by standard surgical, radiotherapeutic, or chemotherapeutic modalities.
Post-transplant lymphoproliferative disorder (PTLD): Management of PTLD deserves special mention as the treatment has undergone major changes over time. The main options for initial treatment are the reduction of immunosuppression, immunotherapy with the CD20 monoclonal antibody (rituximab), chemotherapy, radiation therapy, or a combination of these. The PTLD classifies into four types and treatment varies according to the type.
Malignant neoplasms after transplantation have different clinical features that are responsible for higher mortality. The Israel Penn International Transplant Tumor Registry showed that the stage-specific survival for cancer of colon, lung, breast, prostate, and bladder, was lower in patients after solid organ transplant compared with those without it. The 1-year adjusted survival of recipients with colorectal, prostate and non-small-cell lung cancer were 10%, 40%, and 20%, respectively, compared with 40%, 80%, and 30% in the general population. Farrugia et al. reported that the overall risk of cancer death after transplantation was tenfold as compared to age- and sex-matched population.
Complications because of post-transplant cancer are decreased quality of life, death, and increased healthcare spending.
The solid organ recipients should be counseled and taught to remain vigilant of this potential problem. The National Kidney Foundation conducted a survey about whether transplant recipients remembered receiving information about the risk of cancer and other complications. The results were not promising as only one-third of these patients recalled receiving information from a health care professional about cancer risks before the procedure. One fourth (23%) of all the patients learned about the risk of post-transplant cancer only after their surgery. Filling this void a priority and detailed conversation before transplant and on follow-up visits need to take place. The patients should receive counseling regarding the risk factors that can be controlled or manipulated (e.g., immunosuppressive drugs, untreated viral infections), there is a window of opportunity to prevent post-transplant cancers. Thus, lies the importance of constant patient education. Providing education and screening tools for all patients in the postoperative period ensures an extension of the provider's knowledge into the hands of the patients.
Successful organ transplantation and good quality of life for patients requires all members of the healthcare team to work together to provide bedside care, education, physical and psychosocial support, and continued follow-up examinations. Educating residents, organ transplant coordinators, specialty trained nurses, pharmacists, and mid-level practitioners on the latest research are vital in promoting the best perioperative and postoperative care.
Cancer screening and surveillance should be standard practice for healthcare policies in clinics and hospitals. All members of the team should be made aware of dermatological inspections, sun protection programs, and self-screening tools for all patients as a protocol in the posttransplant period. All the protocols should be standardized.
Transplant nurses arrange follow up for these patients, provide education to the patients and their families, monitor patient status, and provide feedback to the team. Pharmacists counsel patients about side effects, screen for drug-drug interactions, and assess compliance. These measures improve outcomes. [Level 5]
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