In their article “Keratinocyte cancer mortality in kidney transplant recipients,” Shao et al1 describe the absolute and relative mortality burden of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney transplant recipients. In a population-based cohort study in Queensland, Australia, Shao et al estimated keratinocyte cancer death using cause of death ascertained from the state-based death register and excess mortality standardized against the general Australian population. In 1866 kidney transplant recipients, with over 25 934 person-years of follow-up, they identified 36 SCC deaths and only 1 death attributed to BCC. They estimated that 78 per 100 000 kidney transplant recipients die from SCC per year. Keratinocyte cancer death in Queensland, which was almost exclusively SCC, was 23 times in excess of the general population of Australia; 27 times in men and 16 times in women. Their work highlights a dramatic increase in excess death from keratinocyte cancer in kidney recipients compared with the general population. The authors confirmed previously identified pretransplant risk factors for keratinocyte cancer.
The reversed ratio of increased incidence of SCC in kidney transplant recipients, compared with BCC in immunocompetent people, has been well described.2-5 Estimates of keratinocyte cancer incidence in the general population are limited because these cancers, unlike most others, are excluded from statutory reporting requirements in countries with a cancer registry. Nonmelanoma skin cancer mortality is captured by national death registration, and hence is one way of accessing population-based estimates of skin cancer outcomes and burden. The majority of SCC death in keratinocyte cancer deaths is likely generalizable to all mortality estimates for nonmelanoma skin cancers, given the rarity of other skin cancers and the unlikeliness that BCC will cause death. In absolute terms, estimated death rates are likely to be among the highest rates of kidney transplant recipients globally. Queensland has 73% population with European ancestry and experiences high level of UV exposure given its proximity to the equator (21o South latitude). Relative estimates of mortality risk may have limited applicability to kidney transplant populations with similar demographics and environmental exposures, including all of Australia and New Zealand.
Risk factors similar to those identified by Shao et al, male sex, older age, and Caucasian ethnicity, have been described for SCC development in population-based studies. Other risk factors identified in the literature, including fair skin, history of SCC pretransplant, and burden, currency, and duration on immunosuppression,5,6 were not included in this study but are reflected in the demographics provided; 41% of recipients were transplanted over 10 y prior and only 20% of the cohort experienced graft failure. What this study does not tell us is about the timing of intervals of symptoms, investigation, and treatment of keratinocyte cancers that led to death. This kind of information may help us better understand what intervention points may improve patient outcomes. Similar studies of melanoma mortality in kidney transplant recipients, which also identify history of SCC pretransplant and increased dose and duration on immunosuppression as risk factors, suggest that current cancer treatment strategies developed for the general population may not be appropriate for the transplant population.7
Kidney transplant recipients are often excluded from clinical trials that are focused on treating other conditions, despite the commonality of multimorbidity. This includes oncology trials. Studies using novel immunotherapies, including checkpoint inhibitors, justify the exclusion of transplant patients due to concerns about the activation of T-cells responses that may mediate transplant rejection and loss. More recently, there is evidence of the safe use of checkpoint inhibitors in kidney transplant recipients for the treatment of locally advanced SCC while continuing immunosuppression with low-dose prednisone alone. Additionally, clinical trials are underway to better elucidate the benefits and harms of immunotherapy use in kidney transplant recipients with pretreated incurable or metastatic cancers.8,9
SCC treatment can be complicated depending on site and costly, increasingly so when metastatic. SCC in kidney transplant recipients develop earlier, are more aggressive, and at higher risk of metastases than in the general population.2 The benefits of early detection and treatment are well understood. Current clinical guidelines recommend annual screening by qualified health professionals, prioritizing higher risk groups, like those with a history of skin cancer, for referral to dermatologists.10 Shao et al point out the “difficulties in adequately treating a large number of rapidly growing skin cancer simultaneously,” particularly in a setting at such high risk of skin cancer. In Australia, 74% of kidney transplant recipients who had skin cancer removed had a history of 2 or more lesions.4 High-throughput specialist clinics for the provision of dermatology and surgical care in transplant recipients have demonstrably reduced patients out of pocket costs and expedited skin cancer treatments in this same population.11,12 The efficient coordination of surgical, oncology, and nephrology clinicians to ensure early treatment of complicated presentations is paramount for improvement of patient outcomes.
1. Shao E, Betz-Stablein B, Khosrotehrani K, et al. Keratinocyte cancer mortality in kidney transplant recipients. Transplantation. [Epub ahead of print. May 25, 2021]. doi:10.1097/TP.0000000000003827
2. Harwood CA, Mesher D, McGregor JM, et al. A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population. Am J Transplant. 2013;13:119–129.
3. Mackenzie KA, Wells JE, Lynn KL, et al. First and subsequent nonmelanoma skin cancers: incidence and predictors in a population of New Zealand renal transplant recipients. Nephrol Dial Transplant. 2010;25:300–306.
4. Pandeya N, Olsen CM, Whiteman DC. The incidence and multiplicity rates of keratinocyte cancers in Australia. Med J Aust. 2017;207:339–343.
5. Ramsay HM, Fryer AA, Hawley CM, et al. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol. 2002;147:950–956.
6. Gallagher MP, Kelly PJ, Jardine M, et al. Long-term cancer risk of immunosuppressive regimens after kidney transplantation. J Am Soc Nephrol. 2010;21:852–858.
7. Vajdic CM, Chong AH, Kelly PJ, et al. Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study. Am J Transplant. 2014;14:1368–1375.
8. Australian New Zealand Clinical Trials Registry. Nivolumab in renal transplant recipients with poor prognosis cancers—a safety study. Available at https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372928
. Accessed May 11, 2021.
9. Paoluzzi L, Ow TJ. Safe administration of cemiplimab to a kidney transplant patient with locally advanced squamous cell carcinoma of the scalp. Curr Oncol. 2021;28:574–580.
10. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9(suppl 3):S1–155.
11. Gordon LG, Rodriguez-Acevedo AJ, Papier K, et al. The effects of a multidisciplinary high-throughput skin clinic on healthcare costs of organ transplant recipients. J Eur Acad Dermatol Venereol. 2019;33:1290–1296.
12. Papier K, Gordon LG, Khosrotehrani K, et al. Management of organ transplant recipients attending a high-throughput skin cancer surgery and surveillance clinic in Queensland. Br J Dermatol. 2019;180:631–636.