11.1 Epidemiology of keratinocyte cancers in immunosuppressed patients
Intact immunosurveillance is essential for defence against development of skin cancer. Hence, people with conditions affecting the immune system are at increased risk of keratinocyte cancer (KC), whether due to immune-related disease, immune-modulating treatments, or both.
Overview of evidence (non-systematic literature review)[edit source]
Keratinocyte cancer prevalence, incidence and mortality in organ transplant recipients[edit source]
Immunosuppressant drugs prevent organ rejection in organ transplant recipients (OTRs) but greatly increase the risk of cutaneous squamous cell carcinoma (cSCC) in particular, and of basal cell carcinoma (BCC), compared with the general population.
In Australia, available data on KC rates among OTRs are mainly from studies conducted in Queensland. A Queensland cross-sectional study investigated KC risk among kidney and liver transplant recipients (mean age 54 years) immunosuppressed for approximately 9 years, most of whom had a history of KC or actinic keratoses (AKs). It reported that 135 (27%) participants had BCC, cSCC or Bowen’s disease present on dermatological examination (and confirmed histologically within 3 months), while AKs were present in over 80%.
Among Queensland kidney transplant recipients aged over 40 years or immunosuppressed for 10 years or more, and with a history of KC or AK, the estimated annual incidence rates of KC are approximately 120 per 1000 person–years for cSCC and 88 per 1000 person–years for BCC. Estimated annual incidence rates are approximately one-third lower among liver recipients of the same average age and duration of immunosuppression.
Keratinocyte cancer incidence rates are highest among heart transplant and lung transplant recipients, due to their very high immunosuppressant medication levels. The current incidence of cSCC and BCC among lung transplant recipients in Queensland is 201 and 171 persons affected respectively per 1000 person–years. The burden of cSCC and BCC is even higher when incidence calculations account for multiple tumours, which are the norm for affected OTRs.
In OTRs, unlike in the general population, cSCC has a measurable mortality rate because these patients are more likely to have aggressive disease with high rates of invasion. For example, among 17,628 kidney transplant recipients in Australia and New Zealand with 175,084 years of observation followed between 1980 and 2013 inclusive, there were 154 deaths from KC. This is around 50 times the rate of death from KC seen in people in the general population of the same age and sex during the same period: standardised mortality ratio 51; 95% confidence interval (CI) 44–60. Among 619 cardiothoracic transplant patients in an early study in New South Wales, 19 were diagnosed with aggressive cSCCs, and 8 died from uncontrolled local disease or metastasis.
Risk factors for keratinocyte cancer in organ transplant recipients[edit source]
Risk of skin cancer in OTRs is correlated with similar sun exposure-related factors as for immunocompetent patients, including older age, light skin colour and high exposure to ultraviolet (UV) radiation.
The risk of KC in OTRs also depends directly on duration of immunosuppression. In addition, cSCC is associated with independent carcinogenic effects of azathioprine and with voriconazole, a photosensitising fungicide often used in lung transplant recipients.
Patients receiving stem cell transplantation[edit source]
A systematic review of studies to December 2013 showed that bone marrow transplant recipients are at risk of both BCC and cSCC. The 20-year cumulative incidence was 6.5% for BCC and 3.4% for cSCC and risk varied according to the type of primary disease, graft-versus-host disease, duration of immunosuppression, radiation exposure, and T-cell depletion, in addition to skin colour and sex.
These findings are supported by the results of a large case-control study in white US Medicare patients aged over 65 years who had at least one visit to a dermatologist in 2010–2011. Those who had received bone marrow transplantation, especially those with graft-versus-host disease, were at significantly raised risk of both cSCC and BCC compared with those without immune-related disorders.
Patients with rheumatoid arthritis[edit source]
In elderly US Medicare patients who had seen a dermatologist at least once in a 2-year period, those with rheumatoid arthritis (RA) showed a very small overall increase in the risk of cSCC but not BCC, compared with a control group of patients treated for a variety of non-immune-related diseases.
A UK study found that patients with RA treated with either disease-modifying anti-rheumatic drugs (DMARDs) or anti-tumour necrosis factor (anti-TNF) therapy had significantly higher KC risks (up to two-fold higher) than the general population, but there was no evidence that anti-TNF therapy increased risk compared with DMARD. However, the findings of studies in Denmark and Taiwan have suggested that biological therapy for RA is associated with increased KC risk, although the increase was not statistically significant in the Taiwanese study.
Studies assessing the risk of cSCC in patients exposed to biological therapies for RA, compared with biological-naïve patients, have reported inconsistent findings, with significantly increased cSCC risk in one study but not in others.
Patients with psoriasis[edit source]
Biological therapies, including anti-TNF therapies, are increasingly used to treat psoriasis, an autoimmune inflammatory skin disease.
The risk of KC in patients with psoriasis, compared with a control population, was examined in a systematic review of randomised controlled trials, prospective cohort studies and previous systematic reviews to August 2016. Most studies assessing the specific risk of cSCC and BCC in psoriasis patients treated with biologicals, compared with either the general population or biological-naïve patients, reported significant increases in risk of cSCC, but not BCC. However, one study of US patients treated with adalimumab observed increased BCC risk, compared with the general population.
Patients with inflammatory bowel disease[edit source]
The two main forms of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis, affect people from a young age with potentially severe complications, warranting the use of strong and sustained immunosuppression. Immunosuppressive agents used in IBD include potent steroids, thiopurine or its derivatives, and more recently, anti-TNF and anti-interleukin 23 (IL23) biological therapies.
Increased KC incidence has been reported in patients with IBD across a variety of populations, ranging from an approximately 1.5-fold increase in higher-incidence populations like the USA or the Netherlands, to a 9-fold increase in Crohn's disease and a 14-fold increase in ulcerative colitis in a cohort of 2621 patients in the low-incidence Hong Kong population.
In a French prospective national cohort of more than 19,000 patients with IBD, the incidence of KC was raised (by around 10-fold for BCC, 4-fold for cSCC) only in those treated with thiopurine, consistent with findings from a case-control study in the USA. Neither age, sex nor type of IBD appeared to influence the association. Past users of thiopurine continued to be at raised KC risk, pointing to DNA damage as the likely mode of carcinogenesis.
Biological therapies[edit source]
It remains controversial whether the main anti-TNF treatments for IBD (adalimumab and infliximab) increase KC risk, since many biologic-treated patients have also been treated with thiopurines. Newer inhibitors of the IL23-IL17 pathway have yet to be evaluated.
When adalimumab was assessed as a monotherapy versus in combination therapy in a cohort of 1500 patients with Crohn's disease, it did not result in any increased incidence of KC, compared with a 3-fold KC increase with combination therapy with thiopurines. This finding is consistent with a recent meta-analysis of existing clinical trials of anti-TNF therapies in patients with IBD.
Patients with chronic lymphocytic leukaemia[edit source]
Chronic lymphocytic leukaemia (CLL) is a low-grade lymphoproliferative disorder of B cells and is the most common adult leukaemia.
Skin cancers are the most common secondary non-haematological malignancy in patients with CLL, and the risk of KC is increased 5- to 8-fold. Whilst cSCCs comprise the vast majority (at least 90%) of skin cancers in patients with CLL, the rates of BCC are also increased.
Keratinocyte cancers in patients with CLL demonstrate more aggressive behaviour than in other patients, with increased rates of local recurrence, regional and distant metastases and death. An Australian population-based study in people with CLL found that the standardised mortality ratio for skin cancers (KC and melanoma) was the highest for all causes of death. Similarly, a 20-year retrospective study at two academic centres in the USA showed that the risk of death from skin cancer among patients with CLL was as high as that from CLL itself (13% versus 14%).
In terms of surgical management of KC in CLL patients, leukaemic lymphocytic infiltrates around tumours may complicate interpretation of histological margins, especially where tissue is processed by frozen section (e.g. in Mohs micrographic surgery) instead of paraffin sections.
Patients with HIV[edit source]
There is evidence from several cohort studies that human immunodeficiency virus (HIV)-positive patients are at increased risk for KC. The larger cohort study of 6560 HIV-positive patients and 36821 HIV-negative patients found that KC incidence rate was increased two-fold in the HIV-positive group, with the risk of cSCC slightly higher than that of BCC. In this cohort, cSCCs, but not BCCs, were associated with immunodeficiency defined as low CD4 count (<200 cells/µL).
Regular and close skin cancer surveillance should be provided routinely for patients with conditions characterised by immune-system dysregulation, such as HIV and chronic lymphocytic leukaemia.
- Organ transplantation and other conditions associated with immunosuppression – Introduction
- Management of keratinocyte cancer risk in organ transplant recipients
- Strategies to manage keratinocyte cancer in organ transplant recipients
- Organ transplantation and other conditions associated with immunosuppression – Health system implications and discussion
- Yanik EL, Pfeiffer RM, Freedman DM, Weinstock MA, Cahoon EK, Arron ST, et al. Spectrum of Immune-Related Conditions Associated with Risk of Keratinocyte Cancers among Elderly Adults in the United States. Cancer Epidemiol Biomarkers Prev 2017 Jul;26(7):998-1007 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28377416.
- Iannacone MR, Sinnya S, Pandeya N, Isbel N, Campbell S, Fawcett J, et al. Prevalence of Skin Cancer and Related Skin Tumors in High-Risk Kidney and Liver Transplant Recipients in Queensland, Australia. J Invest Dermatol 2016 Jul;136(7):1382-1386 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26968258.
- Plasmeijer EI, Neale RE, de Koning MN, Quint WG, McBride P, Feltkamp MC, et al. Persistence of betapapillomavirus infections as a risk factor for actinic keratoses, precursor to cutaneous squamous cell carcinoma. Cancer Res 2009 Dec 1;69(23):8926-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19903846.
- Krynitz B, Edgren G, Lindelöf B, Baecklund E, Brattström C, Wilczek H, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study. Int J Cancer 2013 Mar 15;132(6):1429-38 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22886725.
- Way M, Marquart L, Chambers DC, Hopkins P et al. Severe burden of multiple incident skin cancers in lung transplant recipients: prospective, population-based study. 2019.
- Garrett GL, Lowenstein SE, Singer JP, He SY, Arron ST. Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013. J Am Acad Dermatol 2016 Jul;75(1):106-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27067869.
- Rosales B, De La Mata N, Vajdic C, Kelly PJ, Wyburn K, Webster AC. Cancer mortality in kidney transplant recipients: an Australian and New Zealand population-based cohort study, 1980-2013. Int J Cancer 2019 Jul 24;doi: 10.1002/ijc.32585.
- Veness MJ, Quinn DI, Ong CS, Keogh AM, Macdonald PS, Cooper SG, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer 1999 Apr 15;85(8):1758-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10223570.
- Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003 Apr 24;348(17):1681-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12711744.
- Iannacone MR, Pandeya N, Isbel N, Campbell S, Fawcett J, Soyer HP, et al. Sun Protection Behavior in Organ Transplant Recipients in Queensland, Australia. Dermatology 2015;231(4):360-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26418864.
- Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC. Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis. Am J Transplant 2016 Dec;16(12):3490-3503 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27163483.
- Tang H, Shi W, Song Y, Han J. Voriconazole exposure and risk of cutaneous squamous cell carcinoma among lung or hematopoietic cell transplant patients: A systematic review and meta-analysis. J Am Acad Dermatol 2018 Aug 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30130598.
- DePry JL, Vyas R, Lazarus HM, Caimi PF, Gerstenblith MR, Bordeaux JS. Cutaneous Malignant Neoplasms in Hematopoietic Cell Transplant Recipients: A Systematic Review. JAMA Dermatol 2015 Jul;151(7):775-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25902409.
- Mercer LK, Green AC, Galloway JB, Davies R, Lunt M, Dixon WG, et al. The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2012 Jun;71(6):869-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22241900.
- Dreyer L, Mellemkjær L, Andersen AR, Bennett P, Poulsen UE, Juulsgaard Ellingsen T, et al. Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry. Ann Rheum Dis 2013 Jan;72(1):79-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22945500.
- Wu CY, Chen DY, Shen JL, Ho HJ, Chen CC, Kuo KN, et al. The risk of cancer in patients with rheumatoid arthritis taking tumor necrosis factor antagonists: a nationwide cohort study. Arthritis Res Ther 2014 Sep 30;16(5):449 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25267341.
- Raaschou P, Simard JF, Holmqvist M, Askling J, ARTIS Study Group.. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ 2013 Apr 8;346:f1939 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23568792.
- Wadström H, Frisell T, Askling J, Anti-Rheumatic Therapy in Sweden (ARTIS) Study Group.. Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical Practice: A Nationwide Cohort Study From Sweden. JAMA Intern Med 2017 Nov 1;177(11):1605-1612 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28975211.
- Peleva E, Exton LS, Kelley K, Kleyn CE, Mason KJ, Smith CH. Risk of cancer in patients with psoriasis on biological therapies: a systematic review. Br J Dermatol 2018 Jan;178(1):103-113 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28722163.
- Papp KA, Poulin Y, Bissonnette R, Bourcier M, Toth D, Rosoph L, et al. Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population. J Am Acad Dermatol 2012 Feb;66(2):e33-45 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20850895.
- Pariser DM, Leonardi CL, Gordon K, Gottlieb AB, Tyring S, Papp KA, et al. Integrated safety analysis: short- and long-term safety profiles of etanercept in patients with psoriasis. J Am Acad Dermatol 2012 Aug;67(2):245-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22015149.
- Asgari MM, Ray GT, Geier JL, Quesenberry CP. Malignancy rates in a large cohort of patients with systemically treated psoriasis in a managed care population. J Am Acad Dermatol 2017 Apr;76(4):632-638 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28162854.
- Leonardi C, Papp K, Strober B, Reich K, Asahina A, Gu Y, et al. The long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials. Am J Clin Dermatol 2011 Oct 1;12(5):321-37 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21834597.
- Long MD, Herfarth HH, Pipkin CA, Porter CQ, Sandler RS, Kappelman MD. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2010 Mar;8(3):268-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20005977.
- van den Heuvel TR, Wintjens DS, Jeuring SF, Wassink MH, Romberg-Camps MJ, Oostenbrug LE, et al. Inflammatory bowel disease, cancer and medication: Cancer risk in the Dutch population-based IBDSL cohort. Int J Cancer 2016 Sep 15;139(6):1270-80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27170593.
- So J, Tang W, Leung WK, Li M, Lo FH, Wong MTL, et al. Cancer Risk in 2621 Chinese Patients with Inflammatory Bowel Disease: A Population-based Cohort Study. Inflamm Bowel Dis 2017 Nov;23(11):2061-2068 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28991855.
- Peyrin-Biroulet L, Khosrotehrani K, Carrat F, Bouvier AM, Chevaux JB, Simon T, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011 Nov;141(5):1621-28.e1-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21708105.
- Osterman MT, Sandborn WJ, Colombel JF, Robinson AM, Lau W, Huang B, et al. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn's disease. Gastroenterology 2014 Apr;146(4):941-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24361468.
- Williams CD, Gajra A, Ganti AK, Kelley MJ. Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer. Cancer 2014 Mar 25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24668613.
- Velez NF, Karia PS, Vartanov AR, Davids MS, Brown JR, Schmults CD. Association of advanced leukemic stage and skin cancer tumor stage with poor skin cancer outcomes in patients with chronic lymphocytic leukemia. JAMA Dermatol 2014 Mar;150(3):280-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24429548.
- Levi F, Randimbison L, Te VC, La Vecchia C. Non-Hodgkin's lymphomas, chronic lymphocytic leukaemias and skin cancers. Br J Cancer 1996 Dec;74(11):1847-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8956805.
- Mehrany K, Weenig RH, Pittelkow MR, Roenigk RK, Otley CC. High recurrence rates of Basal cell carcinoma after mohs surgery in patients with chronic lymphocytic leukemia. Arch Dermatol 2004 Aug;140(8):985-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15313816.
- Mehrany K, Byrd DR, Roenigk RK, Weenig RH, Phillips PK, Nguyen TH, et al. Lymphocytic infiltrates and subclinical epithelial tumor extension in patients with chronic leukemia and solid-organ transplantation. Dermatol Surg 2003 Feb;29(2):129-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12562340.
- Brewer JD, Shanafelt TD, Khezri F, Sosa Seda IM, Zubair AS, Baum CL, et al. Increased incidence and recurrence rates of nonmelanoma skin cancer in patients with non-Hodgkin lymphoma: a Rochester Epidemiology Project population-based study in Minnesota. J Am Acad Dermatol 2015 Feb;72(2):302-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25479909.
- Royle JA, Baade PD, Joske D, Girschik J, Fritschi L. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study. Br J Cancer 2011 Sep 27;105(7):1076-81 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21847118.
- Wee E, Goh MS, Estall V, Tiong A, Webb A, Mitchell C, et al. Retrospective audit of patients referred for further treatment following Mohs surgery for non-melanoma skin cancer. Australas J Dermatol 2018 Jan 18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29349770.
- Hausauer AK, Maurer T, Leslie KS, Parvataneni R, Stuart SE, Chren MM. Recurrence after treatment of cutaneous basal cell and squamous cell carcinomas in patients infected with human immunodeficiency virus. JAMA Dermatol 2013 Feb;149(2):239-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23426494.
- Silverberg MJ, Leyden W, Warton EM, Quesenberry CP Jr, Engels EA, Asgari MM. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst 2013 Mar 6;105(5):350-60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23291375.