11.1 Epidemiology of keratinocyte cancers in immunosuppressed patients

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Clinical practice guidelines for keratinocyte cancer > 11.1 Epidemiology of keratinocyte cancers in immunosuppressed patients


Background

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.[1]

Overview of evidence (non-systematic literature review)

Keratinocyte cancer prevalence, incidence and mortality in organ transplant recipients

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 diseasecSCC in situ (also known as intra-epidermal SCC) present on dermatological examination (and confirmed histologically within 3 months), while AKs were present in over 80%.[2]

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.[3] 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.[4] The current incidence of cSCC and BCC among lung transplant recipients in Queensland is 201 and 171 persons affected respectively per 1000 person–years.[5] 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[6] 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.[7] 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.[8]

Risk factors for keratinocyte cancer in organ transplant recipients

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.[9][10]

The risk of KC in OTRs also depends directly on duration of immunosuppression.[9] In addition, cSCC is associated with independent carcinogenic effects of azathioprine[11] and with voriconazole, a photosensitising fungicide often used in lung transplant recipients.[12]

Patients receiving stem cell transplantation

A systematic review of studies to December 2013 showed that bone marrow transplant recipients are at risk of both BCC and cSCC.[13] 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.[13]

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.[1]

Patients with rheumatoid arthritis

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.[1]

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.[14] However, the findings of studies in Denmark[15] and Taiwan[16] 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[17] but not in others.[14][18]

Similarly, evidence of increased risk of BCC with anti-TNF therapy is also inconsistent, with different studies showing modest[17] or no association.[14]

Patients with psoriasis

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.[19] Most studies assessing the specific risk of cSCC and BCC in psoriasis patients treated with biologicals, compared with either the general population[20][21] or biological-naïve patients,[22] 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.[23]

Patients with inflammatory bowel disease

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[24] or the Netherlands,[25] 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.[26]

Thiopurines

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,[27] consistent with findings from a case-control study in the USA.[24] Neither age, sex nor type of IBD appeared to influence the association.[27] Past users of thiopurine continued to be at raised KC risk, pointing to DNA damage as the likely mode of carcinogenesis.[27]

Biological therapies

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.[28] This finding is consistent with a recent meta-analysis of existing clinical trials of anti-TNF therapies in patients with IBD.[29]

Patients with chronic lymphocytic leukaemia

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.[30][31] Whilst cSCCs comprise the vast majority (at least 90%) of skin cancers in patients with CLL, the rates of BCC are also increased.[31][32]

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.[32][33][34] 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.[35] 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%).[30]

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.[33][36]

Patients with HIV

There is evidence from several cohort studies that human immunodeficiency virus (HIV)-positive patients are at increased risk for KC.[37][38] 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.[38] In this cohort, cSCCs, but not BCCs, were associated with immunodeficiency defined as low CD4 count (<200 cells/µL).


Key point(s)

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.

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References

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