Marina T. van Leeuwen

Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis

BACKGROUND Only a few types of cancer are recognised as being directly related to immune deficiency in people with HIV/AIDS. Large population-based studies in transplant recipients have shown that a wider range of cancers could be associated with immune deficiency. Our aim was to compare cancer incidence in population-based cohort studies of people with HIV/AIDS and people immunosuppressed after solid organ transplantation. METHODS Two investigators independently identified eligible studies through searches of PubMed and reference lists. Random-effects meta-analyses of log standardised incidence ratios (SIRs) were calculated by type of cancer for both immune deficient populations. FINDINGS Seven studies of people with HIV/AIDS (n=444,172) and five of transplant recipients (n=31 977) were included. For 20 of the 28 types of cancer examined, there was a significantly increased incidence in both populations. Most of these were cancers with a known infectious cause, including all three types of AIDS-defining cancer, all HPV-related cancers, as well as Hodgkins lymphoma (HIV/AIDS meta-analysis SIR 11.03, 95% CI 8.43-14.4; transplant 3.89, 2.42-6.26), liver cancer (HIV/AIDS 5.22, 3.32-8.20; transplant 2.13, 1.16-3.91), and stomach cancer (HIV/AIDS 1.90, 1.53-2.36; transplant 2.04, 1.49-2.79). Most common epithelial cancers did not occur at increased rates. INTERPRETATION The similarity of the pattern of increased risk of cancer in the two populations suggests that it is immune deficiency, rather than other risk factors for cancer, that is responsible for the increased risk. Infection-related cancer will probably become an increasingly important complication of long-term HIV infection.

Cancer incidence and risk factors after solid organ transplantation.

Iatrogenic immunosuppression is a unique setting for investigating immune‐related mechanisms of carcinogenesis. Solid organ transplant recipients have a 3‐fold excess risk of cancer relative to the age‐ and sex‐matched general population. Population‐based studies utilizing cancer registry records indicate that a wide range of cancers, mostly those with a viral etiology, occur at excess rates. To date, cancer risk has predominantly been examined in adult kidney transplant recipients in Western countries. It is yet to be established whether a similar incidence profile exists in the long‐term for other solid organ, pediatric and non‐Western transplant recipients. The cancer incidence profile before and after kidney transplantation strongly suggests a relatively minor contribution by both preexisting cancer risk factors and the conditions underlying end‐stage kidney disease, and points to a causal role for immunosuppression. Within‐cohort risk factor analyses have largely been performed on cohorts with voluntary cancer notification, and very few have incorporated biomarkers of the level of immunosuppression, the current receipt of immunosuppressive agents, or genetic risk factors. Because of their markedly high risk of certain cancers, findings from comprehensive studies in transplant recipients have the potential to raise new avenues for investigation into causal mechanisms and preventive measures against immune‐related and infectious causes of cancer.

The pattern of excess cancer in dialysis and transplantation

BACKGROUND After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible. METHODS In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003. RESULTS The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain. CONCLUSIONS In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.

Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study.

Objective To compare cancer incidence in kidney transplant recipients during periods of transplant function (and immunosuppression) and after transplant failure (when immunosuppression is ceased or reduced). Design, setting, and participants Nationwide, population based retrospective cohort study of 8173 Australian kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry who first received a transplant during 1982-2003. Incident cancers were ascertained using linkage with national cancer registry records. Main outcome measures Cancer-specific standardised incidence ratios for periods of transplant function and for dialysis after transplant failure. Incidence was compared between periods using multivariate incidence rate ratios adjusted for current age, sex, and duration of transplantation. Results All cases of Kaposi’s sarcoma occurred during transplant function. Standardised incidence ratios were significantly elevated during transplant function, but not during dialysis after transplant failure, for non-Hodgkin’s lymphoma, lip cancer, and melanoma. For each of these cancers, incidence was significantly lower during dialysis after transplant failure in multivariate analysis (incidence rate ratios 0.20 (95% CI 0.06 to 0.65) for non-Hodgkin’s lymphoma, 0.04 (0.01 to 0.31) for lip cancer, and 0.16 (0.04 to 0.64) for melanoma). In contrast, standardised incidence ratios during dialysis after transplant failure remained significantly elevated for leukaemia and lung cancer, and cancers related to end stage kidney disease (kidney, urinary tract, and thyroid cancers), with thyroid cancer incidence significantly higher during dialysis after transplant failure (incidence rate ratio 6.77 (2.64 to 17.39)). There was no significant difference in incidence by transplant function for other cancers. Conclusions The effect of immunosuppression on cancer risk is rapidly reversible for some, but not all, cancer types. Risk reversal was mainly observed for cancers with a confirmed infectious cause. Risk of other cancers, especially those related to end stage kidney disease, remained significantly increased after reduction of immunosuppression.

Continuing declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy.

Objective:To describe changes in cancer incidence in people with HIV in Australia since the introduction of highly active antiretroviral therapy (HAART). Design:Population-based, retrospective cohort study of people with HIV (n = 20 232) using data linkage between national registers of HIV/AIDS and cancer in 1982–2004. Methods:Age-adjusted and sex-adjusted incidence rate ratios with 95% confidence intervals were calculated to compare site-specific cancer incidence during the early (1996–1999) and late (2000–2004) HAART periods with that prior to HAART (1982–1995). Five-year age-specific, sex-specific, calendar year-specific, and state-specific standardized incidence ratios with 95% confidence interval were also calculated for each period. Results:Incidence of Kaposi sarcoma and non-Hodgkin lymphoma declined significantly (Ptrend < 0.001). Incidence of Hodgkin lymphoma was significantly higher during the early-HAART period (incidence rate ratio 2.34, 95% confidence interval 1.19–4.63) but declined thereafter (Pdiff = 0.014). Incidence of anal cancer was unchanged (Ptrend = 0.451) and remained raised more than 30-fold. Incidence declined significantly for melanoma (Ptrend = 0.041) and prostate cancer (Ptrend = 0.026), and, during the late-HAART period, was lower than in the general population for both cancers. Incidence of colorectal cancer was consistently lower than in the general population. Conclusion:Incidence of Kaposi sarcoma and non-Hodgkin lymphoma has continued to decline among people with HIV in Australia, though it remains very substantially elevated. Incidence of Hodgkin lymphoma may now also be declining. Incidence of anal cancer has remained stable, and it is now the third most common cancer in HIV-infected Australians. Reasons for the reduced incidence of colorectal and prostate cancer, and more recently of melanoma, are unclear.

Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency

Analysis of cancer risk in primary immune deficiency (PID) offers insight into the relationship between immune function and cancer. Data on Australian patients (n = 1132) notified voluntarily to the Australasian Society of Clinical Immunology and Allergy PID Registry (1990-2008) were linked with national death and cancer registries. Person-years of follow-up commenced from up to 15 years before registration on the PID Registry or January 1982, the inception of national cancer registration. Site-specific, 5-year age-, sex-, calendar year-, and state-standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs) were calculated for all cancers except nonmelanocytic skin cancer. During an average of 16 person-years follow-up, a 1.6-fold excess relative risk of cancer was observed (n = 58; SIR 1.60, 95% CI 1.22-2.07) for all PID combined. Relative risk was increased for non-Hodgkin lymphoma (n = 16; SIR 8.82, 95% CI 5.04-14.30), leukemia (n = 4; SIR 5.36, 95% CI 1.46-13.73), and stomach cancer (n = 3; SIR 6.10, 95% CI 1.26-17.84). Excess cancer risk was observed for predominantly antibody deficiencies and other well-defined immunodeficiency syndromes. Results suggest that predominantly antibody deficiencies may be associated with a narrower range of solid cancers than immunodeficiency characterized by predominantly T-cell deficiency, such as iatrogenic and HIV-related immunodeficiency, although this requires confirmation in larger cohorts.

Latitude gradients for lymphoid neoplasm subtypes in Australia support an association with ultraviolet radiation exposure

Given the uncertainty surrounding solar ultraviolet radiation (UVR) exposure and risk of lymphoid neoplasms, we performed an ecological analysis of national Australian data for incident cases diagnosed between 2002 and 2006. Subtype‐specific incidence was examined by latitude band (<29°S, 29–36°S, ≥37°S), a proxy for ambient UVR exposure, using multiple Poisson regression, adjusted for sex, age‐group and calendar year. Incidence increased with distance from the equator for several mature B‐cell non‐Hodgkin lymphomas, including diffuse large B‐cell [incidence rate ratio (IRR) = 1.37; 95% confidence interval (CI): 1.16–1.61 for latitude ≥37°S relative to <29°S], lymphoplasmacytic (IRR = 1.34; 95% CI: 1.12–1.61), mucosa‐associated lymphoid tissue (IRR = 1.32; 95% CI: 0.97–1.80) and mantle cell lymphoma (IRR = 1.29; 95% CI: 1.05–1.58), as well as plasmacytoma (IRR = 1.52; 95% CI: 1.09–2.11) and plasma cell myeloma (IRR = 1.15; 95% CI: 1.03–1.27). A similar pattern was observed for several mature cutaneous T‐cell neoplasms, including primary cutaneous anaplastic large cell lymphoma (IRR = 4.26; 95% CI: 1.85–9.84), mycosis fungoides/Sézary syndrome (IRR = 1.72; 95% CI: 1.20–2.46), and peripheral T‐cell lymphoma not otherwise specified (NOS) (IRR = 1.53; 95% CI: 1.17–2.00). Incidence of mixed cellularity/lymphocyte‐depleted (IRR = 1.60; 95% CI: 1.16–2.20) and nodular sclerosis Hodgkin lymphoma (IRR = 1.57; 95% CI: 1.33–1.85) also increased with distance from the equator. Many of these subtypes have a known association with infection or immune dysregulation. Our findings support a possible protective effect of UVR exposure on the risk of several lymphoid neoplasms, possibly through vitamin D‐related immune modulation critical in lymphomagenesis.

What types of cancers are associated with immune suppression in HIV? Lessons from solid organ transplant recipients.

Purpose of reviewTo examine recently published evidence of cancer risk after solid organ transplantation to gain insight into cancers that are associated with immune suppression in HIV. Recent findingsData from several population-based studies comparing cancer risk in recipients of solid organ transplants with that in the general population have demonstrated increased risk for a broad range of cancers, predominantly those with a known or suspected infectious cause. This increase in risk is independent of cohort aging and probably independent of established behavioral and other risk factors for cancer. Epidemiological risk factor data are limited but appear to indicate a relationship with severity and duration of immune suppression. A recent meta-analysis indicates a striking similarity in the pattern of cancer occurrence in transplant recipients and people with HIV/AIDS. SummaryThe similarity of the increased risk of cancer in these two immunosuppressed populations, who differ with respect to their underlying conditions and lifestyles, is compelling evidence that these cancers are associated with immune deficiency. The mechanisms are not fully understood but appear to be related to impaired immune surveillance. These data challenge the classification of only a narrow range of cancers as associated with immune suppression in people with HIV/AIDS.

Lymphoid neoplasm incidence by WHO subtype in Australia 1982-2006

There are limited data characterizing the subtype‐specific incidence of lymphoid neoplasms in the World Health Organization (WHO) Classification era. Data were obtained on all incident lymphoid neoplasms registered in Australia during 1982–2006. Subtypes were grouped using the InterLymph nested hierarchical classification, based on the 2008 WHO Classification. Temporal trends were examined using Joinpoint regression; average annual percentage change in incidence was computed. Multiple Poisson regression was used to compare incidence by sex and age. The incidence of all non‐Hodgkin lymphoma (NHL) increased by 2.5%/year during 1982–1996 and was stable thereafter. During 1997–2006, several mature B‐ and natural killer (NK)‐/T‐cell NHL subtypes increased in incidence, including diffuse large B‐cell (1.3%/year), follicular (2.5%/year), Burkitt (6.8%/year), marginal zone (13.2%/year), mantle cell (4.2%/year), peripheral T‐cell lymphoma (4.7%/year) and plasmacytoma (7.1%/year). While chronic lymphocytic leukemia incidence was stable, small lymphocytic lymphoma incidence declined (8.1%/year). Hodgkin lymphoma (HL) incidence increased during 1997–2006 (2.2%/year), both classical (4.3%/year) and nodular lymphocyte predominant (12.1%/year) HL. Diagnostic artifact, evidenced by a sustained decline in the incidence of NHL not otherwise specified (NOS; 5.8%/year) and lymphoid neoplasms NOS (5.6%/year), limits the interpretation of temporal trends for some subtypes. A marked male predominance was observed for almost all subtypes. Incidence of mature B‐ and NK‐/T‐cell NHL subtypes increased sharply with age, except for Burkitt lymphoma/leukemia. For HL subtypes, a bimodal age distribution was only evident for nodular sclerosis HL. Variation in incidence patterns over time and by sex and age supports etiological differences between lymphoid neoplasm subtypes.

No excess risk of follicular lymphoma in kidney transplant and HIV-related immunodeficiency

Subtype‐specific incidence patterns in populations at high risk of lymphoma offer insight into lymphomagenesis. The incidence profiles for the 2 most common non‐Hodgkin lymphoma subtypes were compared for 2 immunodeficient populations, adults receiving a kidney transplant 1982–2003 (n = 7,730) or diagnosed with human immunodeficiency virus (HIV) infection 1982–2004 (n = 17,175). National, population–based registries were linked and standardized incidence ratios (SIRs) were computed for each cohort and lymphoma subtype. Risk of diffuse large B‐cell lymphoma was significantly increased after transplantation (SIR 17.83, 95% CI: 13.61–22.95) and after HIV infection (SIR 58.81, 95% CI: 52.59–65.56). Rates of follicular lymphoma (FL) were neither significantly increased nor decreased in transplant recipients (SIR 0.82, 95% CI: 0.10–2.96) and in people with HIV (SIR 1.25, 95% CI: 0.41–2.91). The findings argue against an infectious or other immunodeficiency‐related etiology for FL and clearly differentiate it from diffuse large B‐cell lymphoma.