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Risk of lymphoma subtypes after solid organ transplantation in the United States

Risk of lymphoma subtypes after solid organ transplantation in the United States FULL PAPER British Journal of Cancer (2013) 109, 280–288 | doi: 10.1038/bjc.2013.294 Keywords: non-Hodgkin’s lymphoma; Hodgkin’s lymphoma; transplantation; immunosuppression; Burkitt’s lymphoma; T-cell lymphoma Risk of lymphoma subtypes after solid organ transplantation in the United States ,1,2 3 4 3 3 3 5 C A Clarke , L M Morton , C Lynch , R M Pfeiffer , E C Hall , T M Gibson , D D Weisenburger , 6 6 1 2 3 O Martı´ nez-Maza , S K Hussain , J Yang , E T Chang and E A Engels 1 2 Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538-2334, USA; Division of Epidemiology, Department of Health Research and Policy and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA; 4 5 Department of Epidemiology, University of Iowa, Iowa City, IA, USA; Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA and Department of Epidemiology, University of California, Los Angeles, CA, USA Background: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. Methods: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. Results: The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt’s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (o20 years) and those receiving organs other than kidneys. Conclusion: Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma. Organ transplantation is a lifesaving option for individuals with most common malignancies diagnosed after transplant (Andreone end-stage organ disease, and over 28 000 solid organ transplanta- et al, 2003). Risk in transplant recipients is estimated as 3- to 21- tions are performed yearly in the United States. However, solid fold higher than that in the general population, and perhaps as organ transplant patients must receive intensive long-term much as 120-fold higher among children who receive transplants immunosuppressive therapy to prevent rejection of the transplant, (Kasiske et al, 2004; Busnach et al, 2006; Caillard et al, 2006; Vajdic putting them at high risk of developing post-transplant lympho- et al, 2006; Giordano et al, 2007; Grulich et al, 2007; Serraino et al, proliferative disorders (PTLDs). These disorders include a 2007; Jiang et al, 2008, 2010; Baccarani et al, 2009; Vajdic and van spectrum of potentially deadly lymphoid cell proliferations, Leeuwen, 2009; Quinlan et al, 2010; Engels et al, 2011). The NHL including non-Hodgkin lymphoma (NHL) and Hodgkin lym- risk exhibits a U-shaped pattern over time following transplanta- phoma (HL) (Tsao and Hsi, 2007). The NHL represents one of the tion, with risk being highest in the first year after transplant, falling *Correspondence: Dr CA Clarke; E-mail: tina@cpic.org Received 13 March 2013; revised 30 April 2013; accepted 20 May 2013; published online 11 June 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 280 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER subsequently, and then increasing again at 5 or more years from human subjects research approval at the Health after transplant (van Leeuwen et al, 2009; Quinlan et al, 2011). Resources and Services Administration and the North Carolina HL was once considered aetiologically distinct from NHL, cancer registry. but is now recognised as similar to some B-cell NHL Lymphoma outcomes and follow-up. The NHLs were identified subtypes. Risk of HL among transplant recipients is likely lower in transplant recipients through linkage with cancer registries. than that for NHL, having been reported as 2- to 3.6-fold higher Lymphoma subtypes were classified using International Classifi- than that in the general population (Quinlan et al, 2010; Engels cation of Diseases for Oncology, 3rd edition (ICD-O-3) site and et al, 2011). histology codes according to current International Lymphoma A major gap in our understanding of transplant-related Epidemiology (InterLymph) Consortium consensus guidelines lymphoma involves the spectrum and associated risks of the many (Turner et al, 2010). Transplant recipients were considered at risk histologic subtypes of lymphoma, which are heterogeneous with of lymphoma beginning at the date of transplantation or the start respect to clinical and epidemiologic characteristics (Morton et al, of cancer registry coverage (whichever came later). Hispanics were 2006; Swerdlow et al, 2008). The two prior studies examining the followed beginning in 1992 to correspond to the years for which risk of NHL subtypes among transplant recipients reported general population rates were available for comparison (see below). substantial elevation in the risk of diffuse large B-cell lymphoma Follow-up time ended at the first diagnosis of any lymphoma (DLBCL, the most common subtype in most populations) but no subtype, death, failure of a transplanted organ, subsequent increase for follicular lymphoma (another common subtype in transplant, loss to follow-up, or last date of cancer registry the general population) (Quinlan et al, 2010; Vajdic et al, 2010). coverage (whichever came first). Recipients were considered These studies were hampered by small numbers, especially of at risk separately during successive transplant episodes. Of the uncommon NHL subtypes, and did not examine how the 180 210 distinct transplant episodes, we excluded 1265 because occurrence of NHL subtypes varied by demographic characteristics racial/ethnic information was missing or did not correspond to a or time since transplantation. group for which general population cancer rates were available, Better characterisation of the risk of lymphoma subtypes in and a further 160 episodes occurring among recipients with human transplant recipients would help clinicians caring for these patients, immunodeficiency virus (HIV) infection reported to the SRTR. as different subtypes require different management. This infor- We did not exclude episodes if the recipient had a history of mation would also improve understanding of the causal impor- cancer before transplantation. Altogether, our final analytic cohort tance of immunosuppression. Therefore, we assessed the risks of included 178 785 transplant episodes occurring in 165 734 individual lymphoma subtypes in the recently completed Trans- individuals, 1617 NHL, and 48 HL cases. plant Cancer Match Study (Engels et al, 2011). This large cohort of Statistical analysis. For each lymphoma subtype, we measured the US solid organ transplant recipients, for whom cancer ascertain- ment was conducted uniformly via linkage with population-based risk in transplant recipients relative to the general population using the standardised incidence ratio (SIR, i.e., observed/expected cancer registries, enabled us to quantify the risks of specific subtypes overall and according to recipient age at transplantation, number of cases). Observed numbers were derived from the cancer registry linkages, as described above. Expected numbers type of transplanted organ, and time since transplant. were calculated by applying general population cancer incidence rates obtained from each cancer registry to person-time at risk among transplant recipients, stratified by sex, 5-year age group, MATERIALS AND METHODS race/ethnicity, and calendar year. Rates for whites, blacks, and Asians/Pacific Islanders were derived from participating registries. Transplant cancer match study. The Transplant Cancer Match Rates for Hispanics (available 1992 onward) were derived from the US Surveillance, Epidemiology, and End Results programme, in Study is described in detail elsewhere (http://transplantmatch. cancer.gov) (Engels et al, 2011). In brief, the US Scientific Registry which 8 of the 14 contributing cancer registries participate. The 95% confidence intervals (CIs) around each SIR were derived of Transplant Recipients (SRTR) was linked with 14 US population-based cancer registries. The SRTR includes structured assuming that the observed counts follow a Poisson distribution. We also calculated SIRs and 95% CIs across categories defined data regarding all US solid organ transplants occurring since 1987, including recipient demographic characteristics, reason for trans- by age at transplant, transplanted organ, and successive time intervals (1–360 days, 361–1800 days, and 1801þ days) plant, and characteristics of the transplanted organs. The cancer registries include standardised information regarding patient after transplant. Univariate Poisson regression models were created for each subtype and used to test for heterogeneity across these demographic characteristics and detailed tumour characteristics. Serial record linkages were completed between the SRTR and categories. the following central cancer registries, together covering B42% of In sensitivity analyses we (1) excluded all transplants for which the reported NHL was not the first haematologic malignancy the US transplant patient population: California (years of coverage: 1988–2008), Colorado (1988–2006), Connecticut (1973–2006), reported, and (2) excluded transplants for which there was a gap between date of transplant and the beginning of cancer registry Georgia (1995–2008), Hawaii (1973–2007), Illinois (1986–2007), Iowa (1973–2007), Michigan (1985–2006), New Jersey (1979– coverage. Results from these sensitivity analyses were similar to those from our main analysis and thus are not presented here. All 2006), New York (1976–2007), North Carolina (1990–2007), the Seattle-Puget Sound area of Washington State (1974–2008), CIs and statistical tests were two sided. Texas (1995–2006), and Utah (1973–2008). Record linkages were accomplished using a computer algorithm followed by manual RESULTS review and confirmation of potential matches. Analyses were restricted to transplant recipients residing in geographic areas covered by the cancer registries during the specified time periods. We evaluated 178 785 solid organ transplants in 165 734 individuals, The TCM Study was approved by human subjects research with 791 281 person-years of follow-up. Table 1 describes the review committees at the National Cancer Institute and the demographic characteristics of individuals who received these following cancer registries: California, Colorado, Connecticut, transplants. Of the transplant recipients, 61% were male, and the Georgia, Hawaii, Illinois, Iowa, Michigan, New Jersey, New York, median age at transplant was 47.0 years, with a quarter of patients Seattle-Puget Sound, Texas, and Utah. It was formally exempted under age 35 years at the time of transplant. Recipients were racially www.bjcancer.com | DOI:10.1038/bjc.2013.294 281 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation two-thirds of all post-transplant NHLs with specified subtype, and Table 1. Characteristics of 178,785 solid organ transplants*, United States, 1987–2008 for which the risk was over 13 times higher than in the general population (SIR¼ 13.5, 95% CI: 12.7–14.4). After DLBCL, the next most commonly diagnosed subtype was Burkitt’s lymphoma, Characteristic n (%) for which the risk was B25 times elevated (SIR¼ 24.5, 95% Sex CI: 19.6–30.2). Other B-cell lymphomas with significantly elevated risks included lymphoplasmacytic lymphoma (SIR¼ 2.8, 95% Male 108 805 (60.86) CI: 1.6–4.5) and marginal zone lymphoma of mucosa-associated Female 69 980 (39.14) lymphoid tissue (MALT; SIR¼ 2.8, 95% CI: 1.9–4.0). The risk of Age at transplant, years developing HL was significantly elevated 3.6-fold (SIR¼ 3.6, 95% CI: 2.9–4.4) compared with the general population. 0–19 16 130 ( 9.02) When T-cell lymphomas were considered as a single entity, the 20–34 28 128 (15.73) risk was seven-fold higher than in the general population 35–49 56 700 (31.71) (SIR¼ 7.1, 95% CI: 5.6–8.9; Table 2). Peripheral T-cell lymphomas 50–64 63 798 (35.68) and anaplastic large-cell lymphomas comprised over 80% of the 65þ 14 029 ( 7.85) T-cell lymphomas, with other subtypes occurring rarely. Race/ethnicity Among the T-cell lymphomas, the greatest risk elevation was for hepatosplenic T-cell lymphoma (SIR¼ 100, as noted above). White, non-Hispanic 109 702 (61.36) Other T-cell lymphomas with elevated risks included extranodal Black, non-Hispanic 29 868 (16.71) natural killer (NK)/T-cell lymphomas, nasal type (SIR¼ 15.0, 95% Hispanic 28 446 (15.91) CI: 6.5–29.6), anaplastic large-cell lymphoma (SIR¼ 12.8, 95% CI: Asian/Pacific Islander 10 769 ( 6.02) 9.0–17.7), primary cutaneous anaplastic large-cell lymphoma Transplanted organ (SIR¼ 13.5, 95% CI: 6.2–25.5), and other peripheral T-cell lymphomas (SIR¼ 3.9, 95% CI: 2.7–5). Kidney 104 466 (58.43) Among other specified NHLs, the risk was also elevated for Pancreas or kidney and pancreas 7 991 ( 4.47) precursor B- or T-cell lymphoblastic leukaemia/lymphoma, Liver 38 473 (21.52) compared with the general population (SIR¼ 2.0, 95% Heart and/or lung 25 449 (14.23) CI: 1.23–3.20). In sharp contrast, few cases and no significant Other or multiple 2406 ( 1.35) elevations in risk were observed for follicular lymphoma, Transplant number small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL/SLL), mantle cell lymphoma, or mycosis fungoides/Se´zary’s First 163 071 (91.21) syndrome. Second 14 404 ( 8.06) The risks differed substantially according to the age at Third or higher 1310 ( 0.73) transplant, with a strong inverse relationship between SIRs and age demonstrated for several NHL subtypes and HL (Table 3). Calendar year of transplant Among recipients aged o20 years at the time of trans- 1987–1994 35 280 (19.73) plantation, the risks were strikingly elevated for Burkitt’s 1995–1999 46 890 (26.23) lymphoma (SIR¼ 123, 95% CI: 79.0–183), DLBCL (SIR¼ 379, 2000–2004 57 801 (32.33) 95% CI: 318–447), peripheral T-cell lymphoma (SIR¼ 172, 95% 2005–2008 38 814 (21.71) CI: 69.1–354), and anaplastic large-cell lymphoma (SIR¼ 96.9, 95% CI: 41.8–191). For many subtypes, it was difficult to assess *Includes 178,785 solid organ transplant episodes occurring in 165,734 recipients. gradients in risk by age because there were fewer than three cases diagnosed among those aged o20 years at transplant. Notably, and ethnically diverse, with almost 40% of patients being non-white. however, the risks for most subtypes among individuals aged Z50 Kidney transplants were most common, but 41% of transplants were years at the time of transplantation remained elevated compared of other organs, and 91% were first transplants. with the general population. Through matches with cancer registry records, 1617 NHL Table 4 shows that for some subtypes, the patterns of risk also diagnoses and 48 HL diagnoses among transplant recipients were differed with respect to time since transplant, although for other identified. Of the NHLs, specific histologic subtype was reported subtypes, the numbers were small and differences were not for 1285 (80%). Compared with cases with specified subtypes, significant. The SIRs for DLBCL and anaplastic large-cell NHLs for which histologic subtype was not reported (i.e., ‘NHL, lymphoma showed a U-shaped pattern, with risks highest in the not otherwise specified’) were similar in terms of age, sex, and first year after transplant, lower at 361–1800 days after transplant, organ transplanted, but were significantly (Po0.05) more likely to and slightly higher again 1801þ days after transplant. In contrast, have disease limited to lymph nodes (i.e., nodal) and to have been SIRs for HL, Burkitt’s lymphoma, peripheral T-cell lymphomas, diagnosed in the earlier years of the study (e.g., 1987–1994). and hepatosplenic T-cell lymphoma were not statistically signi- Overall, transplant recipients had over six-fold increased risk of ficantly elevated in the first year after transplant but increased developing any kind of NHL compared with the general population subsequently, with markedly elevated relative risk observed 1801þ (SIR¼ 6.2, 95% CI: 5.9–6.5). Table 2 describes the risk for 19 days after transplant. defined distinct NHL subtypes. Among NHLs for which specific The risk of lymphoma subtypes differed by the type of organ subtypes were reported, 85.5% were B-cell lymphomas and 6.2% transplanted (Table 5). For most subtypes, kidney recipients had were T-cell lymphomas. The NHL subtype with the highest lower SIRs than liver or thoracic organ (heart and/or lung) elevation in risk was hepatosplenic T-cell lymphoma, an recipients (although still elevated compared with the general uncommon NHL subtype for which the risk was elevated 100- population in many instances). However, the number of cases for fold (SIR¼ 100, 95% CI: 33–234) above the general population. many subtypes was small, and risk did not differ significantly by However, this increase was based on only six cases and an organ. The risks for DLBCL and anaplastic large-cell lymphoma incidence rate of less than one per 100 000 person-years. The most were highest among pancreas and kidney/pancreas recipients, common subtype diagnosed was DLBCL, which comprised almost whereas Burkitt’s lymphoma risk was highest among liver and 282 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER Table 2. Overall SIRs for lymphoma subtypes among solid organ transplant recipients, United States, 1987–2008 Incidence rate / Observed 100 000 ICD-O-3 site and histology codes count SIR 95% CI person-years B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 9687, 9826 88 24.5 19.7–30.2 11.1 Chronic lymphocytic lymphoma/ 9670, 9823 36 0.7 0.5–0.9 4.5 small lymphocytic lymphoma Diffuse large B-cell lymphoma 9678–9680, 9684 948 13.5 12.7–14.4 119.8 Follicular lymphoma 9690, 9691, 9695, 9698 38 0.9 0.7–1.3 4.8 Lymphoplasmacytic lymphoma 9671, 9761 16 2.8 1.6–4.5 2.0 Mantle cell 9673 3 0.4 0.1–1.0 0.4 Marginal zone 9689, 9699, 9760, 9764, 9699, 9715 35 2.2 1.6–3.1 4.4 Splenic/nodal marginal zone 9689, 9699 (site 77.0–77.9), 9715 (site 77.0–77.9) 6 1.1 0.4–2.4 0.8 MALT type 9760, 9764, 9699 (excl site 77.0–77.9), 9715 (excl site 77.0–77.9) 29 2.8 1.9–4.0 3.7 T-cell lymphoma subtype Peripheral T-cell lymphoma 9702, 9705, 9708, 9709, 9717 30 3.9 2.7–5.6 3.8 ALCL 9714 36 12.8 9.0–17.7 4.5 Primary cutaneous ALCL 9718 9 13.5 6.2–25.5 1.1 Mycosis fungoides/Se´ zary’s 9700, 9701 8 1.6 0.7–3.2 1.0 syndrome Hepatosplenic T-cell lymphoma 9716 5 100 33–234 0.6 NK/T-cell lymphoma 9719 8 15.0 6.5–29.6 1.0 All T-cell lymphoma combined 9702–9718 80 7.1 5.7–8.9 10.1 Precursor B- or T-cell 9727–9729, 9835–9837 19 2.0 1.2–3.2 2.4 lymphoblastic leukaemia/lymphoma NHL, other 9762, 9827, 9831–9834, 9940, 9948 9 1.7 0.8–3.3 1.1 NHL, not otherwise specified 9590–9595, 9675, 9820, 9970 332 10.2 9.1–11.3 42.0 All NHL 9590–9595, 9670, 9671, 9673, 9675, 9678–9680, 9684, 9687, 1617 6.2 5.9–6.5 204.4 9689, 9690, 9691, 9695, 9698, 9699, 9700, 9701, 9702, 9705, 9708, 9709, 9714, 9715, 9716, 9717, 9718, 9719, 9727–9729, 9760, 9761, 9762, 9764, 9820, 9823, 9826, 9827, 9831–9837, 9940, 9948, 9970 Hodgkin’s lymphoma (excluding nodular lymphocyte 9650–9655, 9661–9665, 9667 83 3.6 2.9–4.4 10.5 predominant type) Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; ICD-O-3¼ International Classification of Diseases for Oncology, 3rd edition; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio. Bold indicates SIRs significantly different from 1 at Po0.05. thoracic organ recipients. None of the recipients who developed and anaplastic large-cell lymphoma (both systemic and primary hepatosplenic T-cell lymphoma received a liver transplant, rather, cutaneous forms). For DLBCL and Burkitt’s lymphoma, which four of the six recipients received kidneys. were the most common lymphoma subtypes after transplant, the The patterns for NHL overall according to age, organ type, and relative risks were most strongly pronounced among transplant time since transplant generally mirrored those observed for patients under age 20 years, and differed according to the type DLBCL, the most common subtype (Tables 3–5). Similarly, the of organ transplanted. We also observed moderately elevated patterns of risk of unclassified lymphoma (NHL, not otherwise risks (i.e., 2- to 3-fold higher than the general population) for HL, specified) were also similar to those observed for DLBCL. lymphoplasmacytic lymphomas, precursor B- or T-cell lympho- blastic leukaemia/lymphoma, other T-cell lymphomas, and marginal zone lymphoma of MALT type, whereas the risks were not increased for follicular or mantle cell lymphomas, CLL/SLL, or DISCUSSION mycosis fungoides/Sezary’s syndrome. The mechanisms explaining the different spectrum of Non-Hodgkin’s lymphoma is among the most common malig- lymphoma subtypes among transplant patients compared with nancies diagnosed among solid organ transplant recipients. the general population include immunosuppression, including the Overall, the risk for NHL is six-fold higher following transplanta- early, intense induction phase and the later maintenance phase; tion than in the general population, but in this large, population- chronic immune activation because of the presence of donor organ based study we demonstrate that the risks vary dramatically tissue; or the combined effects of these, resulting in long-term, by lymphoma subtype. Elevated risks were particularly striking chronic immune dysfunction. The lymphoma subtypes for which (410-fold) for hepatosplenic T-cell lymphoma, Burkitt’s the risk is elevated are similar to those that are increased in lymphoma, extranodal NK/T-cell lymphoma nasal type, DLBCL, HIV-infected patients (Mbulaiteye et al, 2003; Biggar et al, 2007; www.bjcancer.com | DOI:10.1038/bjc.2013.294 283 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation Table 3. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by age at transplant year, United States, 1987–2008 Age at transplant year 0–19 20–34 35–49 50–64 65þ Poisson 95% 95% 95% 95% 95% Subtype n SIR CI n SIR CI n SIR CI n SIR CI n SIR CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 24 123 79–183 16 39.7 22.7–64.4 21 17.7 10.9–27.0 24 16.7 10.7–24.9 3 8.1 1.7–23.8 o0.0001 Chronic lymphocytic lymphoma /small o3 77.2 2.0–430.2 o3 2.4 0.1–13.6 5 0.6 0.2–1.5 23 0.7 0.4–1.0 6 0.5 0.2–1.0 0.05 lymphocytic lymphoma Diffuse large B-cell lymphoma 138 379 318–447 135 40.3 33.8–47.7 249 15.6 13.7–17.6 348 9.4 8.4–10.5 78 5.8 4.6–7.3 o0.0001 Follicular lymphoma o3 36.6 4.4–132 4 3.4 0.9–8.8 8 0.8 0.4–1.6 20 0.9 0.5–1.4 4 0.6 0.2–1.6 0.0025 Lymphoplasmacytic lymphoma 0 0.0 0–1124 0 0.0 0.0–55.9 3 3.5 0.7–10.3 8 2.4 1.0–4.7 5 3.5 1.1–8.1 0.91 Mantle cell 0 0.0 0–2583 0 0.0 0.0–52.4 0 0.0 0.0–2.7 o3 0.4 0.1–1.4 o3 0.5 0.0–3.1 – Marginal zone 0 0.0 0–111 5 12.8 4.2–29.9 13 4.1 2.2–7.1 9 1.0 0.5–1.9 8 2.5 1.1–4.9 0.0003 Splenic/nodal marginal zone 0 0.0 0–463 3 30.7 6.3–89.8 o3 1.0 0.0–5.7 o3 0.3 0.0–1.8 o3 0.8 0.0–4.7 0.0022 MALT type 0 0.0 0–147 o3 6.8 0.8–24.7 12 5.5 2.9–9.7 8 1.4 0.6–2.7 7 3.5 1.4–7.1 0.02 T-cell lymphoma subtype Peripheral T-cell lymphoma 7 172 69–354 4 12.9 3.5–33.1 6 3.5 1.3–7.7 9 2.1 1.0–4.1 4 2.9 0.8–7.5 o0.0001 ALCL 8 96.9 41.8–191 6 27.7 10.2–60.4 8 10.8 4.7–21.4 14 10.1 5.5–17.0 0 0.0 0.0–9.3 o0.0001 Primary cutaneous ALCL o3 127 3–706 0 0.0 0.0–114.6 o3 12.7 1.5–45.9 4 11.2 3.1–28.7 o3 17.5 2.1–63.4 0.43 Mycosis fungoides/ Se´ zary’s syndrome o3 33.3 0.8–185 0 0.0 0.0–14.2 4 3.1 0.8–7.9 o3 0.8 0.1–2.8 o3 1.4 0.0–7.6 0.10 Hepatosplenic T-cell lymphoma o3 269 7–1501 0 0.0 0.0–387.7 o3 109 13–393 o3 131 16–472 0 0.0 0.0–1256.2 0.50 NK/TCL, nasal type 0 0.0 0–316.0 o3 17.4 0.4–96.9 o3 6.2 0.2–34.6 6 25.9 9.5–56.5 0 0.0 0.0–52.2 0.28 All T-cell lymphoma 17 126 73–202 10 17.5 8.4–32.2 18 6.8 4.0–10.8 29 4.8 3.2–6.9 6 3.2 1.2–6.9 o0.0001 Precursor B- or T- cell lymphoblastic 7 3.2 1.3–6.6 3 3.0 0.6–8.6 4 1.9 0.5–4.8 5 1.6 0.5–3.7 0 0.0 0.0–4.8 0.27 leukaemia/lymphoma NHL, other o3 79.0 2.0–440 o3 4.9 0.1–27.5 3 2.0 0.4–5.9 4 1.4 0.4–3.7 0 0.0 0.0–4.8 0.05 NHL, not otherwise specified 39 266 189–363 40 26.3 18.8–35.8 93 13.0 10.5–15.9 132 7.6 6.4–9.0 28 4.4 2.9–6.4 o0.0001 All NHL 230 72.1 63.1–82.1 216 22.8 19.9–26.1 422 7.7 7.0–8.5 609 4.2 3.9–4.6 140 2.8 2.4–3.3 o0.0001 Hodgkin’s lymphoma 20 14.1 8.6–21.8 16 3.6 2.0–5.8 21 3.0 1.9–4.6 24 2.9 1.9–4.3 o3 1.0 0.1–3.5 o0.0001 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. ‘–’ Indicates too few cases to estimate heterogeneity. Bold indicates SIRs significantly different from 1 at Po0.05. Engels et al, 2008; Vajdic et al, 2010), another population EBV seronegative at transplantation, which puts them at risk of experiencing both chronic immunosuppression and immune subsequent primary EBV infection and PTLD (Jenson, 2011; activation. Investigators in the United States and Australia have Quinlan et al, 2011). For Burkitt’s lymphoma, which is also an demonstrated especially elevated risks among HIV-infected aggressive lymphoma, the risk was similarly highest in children, individuals for ‘high-grade’ NHL subtypes as a group (SIR B50– but was not elevated in the first year after transplant and rose with 110) and for DLBCL (SIRs 25–100), Burkitt’s lymphoma (SIRs 50– time since transplant. Of interest, only 40–60% of HIV-associated 140), and T-cell lymphomas (SIR B15) (Mbulaiteye et al, 2003; Burkitt’s lymphoma is EBV related (Carbone et al, 2009). We were Engels et al, 2006; van Leeuwen et al, 2009; Vajdic et al, 2010). In unable to separate EBV-defined cases, and it is possible that the age contrast, follicular or ‘low-grade’ lymphoma risks were not higher and latency patterns that we observed reflect mixed occurrence for than in the general population in any of the transplant or HIV- EBV-positive and -negative forms of Burkitt’s lymphoma after infected groups (Mbulaiteye et al, 2003; Quinlan et al, 2010; Vajdic transplant (Carbone et al, 2009). Transplant-related cases of HL et al, 2010). The overall relative risks observed here are lower than are also commonly EBV positive (Bierman et al, 1996; Knight et al, those observed in HIV-infected populations, perhaps because of 2009), and in our study, HL risk also increased with time since the different pattern of immunosuppression or the different type of transplant. immune stimulus conferred by a donor organ than associated with We also observed statistically significantly elevated risks of HIV infection. marginal zone lymphomas of MALT type and lymphoplasmacytic These data are informative with regard to several aspects of lymphoma, although the magnitudes of elevation were lower than lymphomagenesis for specific subtypes. For DLBCL, our observa- those for DLBCL and Burkitt’s lymphoma. Outside of the tions are consistent with the known role of Epstein–Barr virus transplant setting, these subtypes are thought to arise under (EBV)-driven B-cell expansion under conditions of intense conditions of persistent immune stimulation by chronic microbial immunosuppression, especially in children. Epstein–Barr virus is infections (e.g., Helicobacter pylori for gastric MALT type detected in the tumour cells of most transplant-related DLBCLs lymphoma, hepatitis C virus for lymphoplasmacytic lymphoma) (Carbone et al, 2009). We found that the risk of developing DLBCL (Engels, 2007; Giordano et al, 2007; de Sanjose et al, 2008). was concentrated in children (ages 0–19 years), and was highest in Transplant-related immunosuppression may increase microbial the first year after transplant. These findings agree with previous activity or modulate the immune response against these micro- reports of transplant-related NHL overall and PTLD (Opelz et al, organisms. In contrast, for other indolent B-cell lymphomas such 2009; Vajdic and van Leeuwen, 2009) and are expected, given that as follicular lymphoma and CLL/SLL, our data are not suggestive of DLBCL comprises a large fraction of PTLD. Children are often major roles for the types of immunosuppression, immune 284 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER Table 4. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by time since transplant, United States, 1987–2008 Time since transplant 1–360 days 361–1800 days 1801þ days Poisson Subtype n SIR 95% CI n SIR 95% CI n SIR 95% CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia o3 3.3 0.4–11.8 54 31.7 23.8–41.3 32 25.0 17.1–35.3 o0.0001 Chronic lymphocytic lymphoma/small 11 1.4 0.7–2.4 12 0.5 0.3–0.9 13 0.6 0.3–1.0 0.05 lymphocytic lymphoma Diffuse large B-cell lymphoma 335 30.1 26.9–33.5 305 9.4 8.4–10.5 308 11.6 10.4–13.0 o0.0001 Follicular lymphoma 13 2.1 1.1–3.5 8 0.4 0.2–0.9 17 1.1 0.6–1.8 0.0014 Lymphoplasmacytic lymphoma 3 3.5 0.7–10.4 6 2.3 0.9–5.1 7 3.0 1.2–6.2 0.81 Mantle cell o3 0.8 0.0–4.7 o3 0.3 0.0–1.5 o3 0.3 0.0–1.6 0.71 Marginal zone 6 2.7 1.0–5.9 13 1.9 1.0–3.2 16 2.4 1.4–3.9 0.69 Splenic/nodal marginal zone o3 1.3 0.0–7.5 o3 0.4 0.0–2.4 4 1.7 0.5–4.4 0.38 MALT type 5 3.4 1.1–7.9 12 2.6 1.4–4.6 12 2.8 1.5–4.9 0.89 T-cell lymphoma subtype Peripheral T-cell lymphoma o3 1.7 0.2–6.2 11 3.2 1.6–5.7 17 5.7 3.3–9.1 0.11 ALCL 15 32.8 18.4–54.1 5 3.7 1.2–8.7 16 15.6 8.9–25.4 o0.0001 Primary cutaneous ALCL 3 32.4 6.7–94.7 o3 3.5 0.1–19.6 5 17.1 5.6–40.0 0.08 Mycosis fungoides/Se´ zary’s syndrome o3 2.4 0.3–8.7 o3 0.8 0.1–3.1 4 2.3 0.6–5.8 0.42 Hepatosplenic T-cell lymphoma 0 0.0 0.0–451.4 o3 42.7 1.1–238.0 4 219 60–560 0.10 NK/TCL, nasal type o3 11.9 0.3–66.33 3 12.3 2.6–36.1 4 19.4 5.3–48.6 0.81 All T-cell lymphoma 20 11.5 7.0–17.8 18 3.5 2.1–5.5 42 9.7 7.0–13.1 o0.0001 Precursor B- or T-cell lymphoblastic o3 1.2 0.1–4.2 11 2.4 1.2–4.3 6 2.0 0.7–4.3 0.59 leukaemia/lymphoma NHL, other 0 0.0 0.0–4.3 5 2.0 0.7–4.7 4 2.1 0.6–5.4 0.20 NHL, not otherwise specified 115 20.2 16.7–24.3 124 7.8 6.5–9.3 93 8.4 6.8–10.3 o0.0001 All NHL 511 12.4 11.3–13.5 561 4.6 4.3–5.0 545 5.5 5.0–6.0 o0.0001 Hodgkin’s lymphoma 6 1.4 0.5–3.1 36 3.2 2.2–4.4 41 5.4 3.9–7.3 0.001 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. Bold indicates SIRs significantly different from 1 at Po0.05. activation, or other immune disturbances experienced by trans- young transplant recipients. This pattern probably reflects the plant recipients. contribution of primary EBV infection in younger recipients, as Although T-cell lymphomas constituted a small proportion of well as a countervailing age-related rise in NHL incidence in the NHLs in this transplant population, we observed very high relative general population due to other mechanisms. Although we risks of certain T-cell subtypes, including hepatosplenic T-cell confirmed a U-shaped pattern in overall NHL risk over time, a lymphoma and both systemic and primary cutaneous anaplastic pattern previously observed by others (van Leeuwen et al, 2009; large-cell lymphomas. For anaplastic large-cell lymphoma, relative Quinlan et al, 2011), we did not find a consistent pattern of risk risks were markedly elevated in the first year after transplant. Of across all the specific subtypes. Intense, T cell-depleting induction interest, EBV is not generally thought to play an important role in immunosuppressive agents used at the time of transplantation may the aetiology of T-cell PTLD (Engels, 2007). Although the explain why the relative risks of DLBCL and systemic and exceedingly rare hepatosplenic T-cell lymphoma is well recognised cutaneous anaplastic large-cell lymphoma were highest nearer the as a type of PTLD, EBV is infrequently detected in tumour cells of time of transplant. In contrast, the relative risk of Burkitt’s this malignancy (Engels, 2007). The very high relative risks of lymphoma increased with longer time since transplant. Among hepatosplenic T-cell and anaplastic large-cell lymphomas observed older recipients and among recipients many years post transplant, here after transplant, but not in HIV-infected individuals lymphoma occurrence may be caused by some combination of age- (Opelz and Dohler, 2004; LaCasce, 2006), may suggest that unique related immune senescence, immunosuppression-related immune aspects of transplant-associated immune disturbance are aetiolo- dysfunction, and chronic antigenic stimulation from the trans- gically important. Inflammatory and anti-inflammatory activity are planted graft or infection (Opelz and Dohler, 2004; Vajdic and van of interest because of the apparent association of hepatosplenic Leeuwen, 2009; van Leeuwen et al, 2009). T-cell lymphomas with use of tumour necrosis factor-a (TNF-a) Our analysis is the first to assess lymphoma subtype occurrence inhibitors for Crohn’s disease, arthritis, and other autoimmune by the type of organ transplanted. The relative risk of DLBCL was diseases (Hellgren et al, 2010; Deepak et al, 2013; Mason and substantially higher among pancreas and pancreas/kidney recipi- Siegel, 2013). It is also interesting that none of the hepatosplenic ents than recipients of other organs, and Burkitt’s lymphoma risk T-cell lymphomas occurred in liver recipients, among whom the was highest among recipients of liver and thoracic organ (heart donor organ provides a strong and sustained local immune and/or lung) transplants. Most prior studies of post-transplant stimulus. cancer risk have focussed on kidney recipients, but some have Our data also demonstrate substantial variation in the risk of reported higher risks of overall NHL for small intestine or lung lymphoma subtypes according to age and time since transplant. In recipients than heart, liver, or kidney recipients (LaCasce, 2006; general, SIRs for most lymphoma subtypes were elevated among Tsao and Hsi, 2007). In the Collaborative Transplant Study, PTLD www.bjcancer.com | DOI:10.1038/bjc.2013.294 285 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation Table 5. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by transplanted organ, United States, 1987–2008 Transplanted organ Pancreas or kidney and Heart Kidney pancreas Liver and/or lung Other or multiple Poisson 95% 95% 95% 95% 95% Subtype n SIR CI n SIR CI n SIR CI n SIR CI n SIR CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 29 14.4 9.7–20.7 o3 7.4 0.2–41.1 38 47.1 33.3–64.6 20 33.0 20.2–51.0 0 0.0 0.0–116.0 o0.0001 Chronic lymphocytic lymphoma/small 18 0.7 0.4–1.1 0 0.0 0.0–4.4 10 0.8 0.4–1.5 8 0.6 0.3–1.2 0 0.0 0.0–8.5 0.73 lymphocytic lymphoma Diffuse large B-cell lymphoma 411 11.0 9.9–12.1 55 32.6 24.6–42.5 215 13.1 11.4–15.0 254 18.2 16.0–20.6 13 22.5 12.0–38.5 o0.0001 Follicular lymphoma 17 0.8 0.5–1.3 0 0.0 0.0–3.5 15 1.5 0.8–2.5 6 0.7 0.3–1.6 0 0.0 0.0–10.6 0.18 Lymphoplasmacytic lymphoma 10 3.5 1.7–6.4 0 0.0 0.0–42.4 o3 0.7 0.0–4.1 5 3.7 1.2–8.6 0 0.0 0.0–79.4 0.34 Mantle cell o3 0.5 0.1–1.8 0 0.0 0.0–24.1 o3 0.5 0.0–2.7 0 0.0 0.0–1.8 0 0.0 0.0–49.0 0.76 Marginal zone 16 1.9 1.1–3.1 o3 3.0 0.1–16.6 12 3.1 1.6–5.4 5 1.7 0.5–3.9 o3 7.2 0.2–40.1 0.54 Splenic/nodal marginal zone 4 1.4 0.4–3.6 0 0.0 0.0–34.6 0 0.0 0.0–2.7 o3 1.8 0.2–6.5 0 0.0 0.0–73.5 0.41 MALT type 12 2.2 1.1–3.8 o3 4.4 0.1–24.4 12 4.8 2.5–8.4 3 1.6 0.3–4.6 o3 11.3 0.3–62.7 0.16 T-cell lymphoma subtype Peripheral T-cell lymphoma 15 3.6 2.0–5.9 o3 5.7 0.1–31.7 8 4.7 2.0–9.3 6 4.1 1.5–8.9 0 0.0 0.0–55.8 0.90 ALCL 14 9.2 5.0–15.4 o3 24.0 2.9–86.7 9 14.4 6.6–27.3 10 18.1 8.7–33.2 o3 42.9 1.1–239.2 0.33 Primary cutaneous ALCL 4 11.3 3.1–28.9 0 0.0 0.0–190.2 3 19.2 4.0–56.1 o3 15.1 1.8–54.4 0 0.0 0.0–572.4 0.88 Mycosis fungoides/Se´ zary’s syndrome o3 0.7 0.1–2.6 o3 8.2 0.2–45.7 3 2.8 0.6–8.2 o3 2.0 0.3–7.4 0 0.0 0.0–93.1 0.37 Hepatosplenic T-cell lymphoma 4 131 36–334 0 0.0 0.0– o3 109 3–608 0 0.0 0.0–481.6 0 0.0 0.0– – 1753.0 12027.9 NK/TCL, nasal type 6 19.5 7.1–42.4 0 0.0 0.0–216.0 0 0.0 0.0–31.2 o3 23.9 2.9–86.3 0 0.0 0.0–725.5 – All T-cell lymphoma 37 6.0 4.2–8.3 3 10.6 2.2–31.1 21 8.4 5.2–12.8 18 8.2 4.9–13.0 o3 10.4 0.3–57.7 0.63 Precursor B- or T-cell lymphoblastic leukaemia/ 7 1.4 0.6–3.0 0 0.0 0.0–14.3 7 2.9 1.2–6.0 4 2.4 0.7–6.3 o3 8.8 0.2–49.0 0.36 lymphoma NHL, other 4 1.5 0.4–3.8 o3 6.2 0.2–34.7 o3 0.8 0.0–4.6 3 2.7 0.6–7.8 0 0.0 0.0–84.1 0.64 NHL, not otherwise specified 126 7.3 6.1–8.7 22 32.0 20.1–48.5 76 10.3 8.1–12.8 102 14.6 11.9–17.7 6 25.8 9.5–56.2 o0.0001 All NHL 684 5.0 4.6–5.4 84 14.4 11.5–17.9 398 6.4 5.8–7.1 429 7.7 7.0–8.5 22 10.1 6.3–15.3 o0.0001 Hodgkin’s lymphoma 48 3.6 2.6–4.7 o3 2.0 0.2–7.2 14 3.0 1.6–5.0 18 4.7 2.8–7.4 o3 5.5 0.1–30.9 0.61 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. ‘–’ Indicates too few cases to estimate heterogeneity. risk was substantially higher among heart/lung and lung recipients 2012) and, moreover, suggest a specific range of lymphoma than among other recipients (Opelz and Dohler, 2004). Variation subtypes as differential diagnoses among such patients. Correct in the risk of DLBCL and other subtypes by organ type may relate diagnosis of subtype is important for management of post- to differences in immunosuppressive regimens or the intensity of transplant lymphoma, most importantly for planning therapeutic immunosuppression. Along these lines, some studies have shown regimen, which varies substantially by specific lymphoma subtype. that overall NHL risk is higher with certain induction immuno- This study has several important strengths. It is the first cohort suppression agents, particularly monoclonal anti-CD3 antibody study of transplant recipients to have a large enough number of (Bustami et al, 2004; Dharnidharka et al, 2012). Among HIV- incident lymphoma cases to allow assessing risks separately for a infected patients, the risk of DLBCL also has been shown to wide spectrum of subtypes. Prior efforts to quantify these risks correlate with the degree of immunosuppression as reflected by have been limited by lack of data on lymphoma subtypes, or small CD4 count (Biggar et al, 2007). Alternatively, it is possible that size and restriction to special subgroups of transplant patients, for different transplanted organs confer different levels of chronic example, kidney recipients (Vajdic et al, 2010) or Medicare antigen stimulation relevant to lymphomagenesis. beneficiaries over age 65 years (Quinlan et al, 2010). Our cohort Although DLBCL is the most commonly diagnosed B-cell included a well-defined, population-based sample of the US malignancy in the general population, it represents only 25–30% of transplant population, and linkage with corresponding popula- all NHL cases (Morton et al, 2006), whereas it comprises over half tion-based cancer registries allowed for highly complete, uniform of all transplant-related NHLs. Follicular lymphoma and CLL/SLL cancer ascertainment. each comprise B15–20% of NHLs diagnosed in the general Among the study’s limitations, we note that lymphoma subtype population, but o3% of NHL cases in our transplant cohort. classifications were derived from cancer registry abstractions of Notably, transplant recipients thus have higher proportions of medical records, which may not have been standard and may have aggressive subtypes and lower proportions of indolent B-cell been affected by changes in lymphoma diagnostic practice over lymphomas. Because many of the subtypes with elevated risk are time. Our prior studies of cancer registry classification of rare in the general population, our results underscore the lymphoma subtypes suggest good reliability for some subtypes importance of expert haematopathologic workup of suspicious (e.g., DLBCL, follicular lymphoma) (Clarke et al, 2004, 2006). lymphoproliferations among transplant patients (Jagadeesh et al, However, misclassification would be more likely for less common 286 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER NHL subtypes and for cases diagnosed in the earlier years of this Cancer Research Center in Seattle, WA. We gratefully acknowledge study before widespread dissemination of the international the support and assistance provided by individuals at the Health consensus guidelines (Clarke et al, 2004, 2006). In addition, we Resources and Services Administration (including Monica Lin), the could not examine risks across the full spectrum of PTLDs, because SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), US cancer registries collect information only for cases deemed and the following cancer registries: the states of California malignant by a pathologist. Despite the large number of NHL (Christina Clarke), Colorado (Jack Finch), Connecticut (Lou cases, we did not have adequate numbers of rare subtypes, Gonsalves), Florida (Brad Wohler), Georgia (Rana Bayakly), including most T-cell lymphomas, to reliably assess risk according Hawaii (Marc Goodman), Iowa (Charles Lynch), Illinois (Lori to age or time since transplant. We note that our estimated risk for Koch), Michigan (Glenn Copeland), New Jersey (Karen Pawlish, overall NHL included CLL, which is now understood to be the Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika same entity as SLL (Turner et al, 2010). Inclusion of CLL/SLL Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the decreased the SIR for overall NHL, which affects comparisons with Seattle-Puget Sound area of Washington (Margaret Madeleine). previous reports (Kasiske et al, 2004; Caillard et al, 2006; Vajdic We also thank analysts at Information Management Services for et al, 2006; Giordano et al, 2007; Serraino et al, 2007; Jiang et al, programming support (David Castenson, Ruth Parsons). 2008, 2010; Baccarani et al, 2009; Quinlan et al, 2010; Engels et al, 2011). Finally, we lacked information on tumour EBV status, and CONFLICT OF INTEREST hence we could not separately examine the risk for EBV-defined lymphoma subtypes. In conclusion, we found substantial differences in the risk for The authors declare no conflict of interest. individual lymphoma subtypes and varying patterns in association with age, transplanted organ, and time since transplantation. These results highlight that NHL should not be considered a single entity DISCLAIMER in studies of lymphoid malignancy or PTLD after transplant. There is a characteristic clinical spectrum of NHL subtypes among The ideas and opinions expressed herein are those of the authors transplant recipients. Because lymphoma treatment varies by and endorsement by the National Cancer Institute, Health subtype, patients suspected of having lymphoma should receive a Resources and Services Administration, SRTR, the Centers for detailed haematopathologic workup. Our findings also provide new Disease Control and Prevention, and individual state cancer insight into the importance of immunosuppression for the registries or their Contractors and Subcontractors is not intended development of some lymphoma subtypes. 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Am J Transplant 4: 905–913. 114: 630–637. Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW van Leeuwen MT, Vajdic CM, Middleton MG, McDonald AM, Law M, (2009) Lymphoma after solid organ transplantation: risk, response Kaldor JM, Grulich AE (2009) Continuing declines in some but not all to therapy, and survival at a transplantation center. J Clin Oncol 27: HIV-associated cancers in Australia after widespread use of antiretroviral 3354–3362. therapy. AIDS 23: 2183–2190. LaCasce AS (2006) Post-transplant lymphoproliferative disorders. Oncologist 11: 674–680. Mason M, Siegel CA (2013) Do inflammatory bowel disease therapies cause This work is published under the standard license to publish agree- cancer? Inflamm Bowel Dis 19(6): 1306–1321. ment. After 12 months the work will become freely available and Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA (2003) Immune deficiency the license terms will switch to a Creative Commons Attribution- and risk for malignancy among persons with AIDS. J Acquir Immune Defic NonCommercial-Share Alike 3.0 Unported License. Syndr 32: 527–533. 288 www.bjcancer.com | DOI:10.1038/bjc.2013.294 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Risk of lymphoma subtypes after solid organ transplantation in the United States

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Springer Journals
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Copyright © 2013 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
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10.1038/bjc.2013.294
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Abstract

FULL PAPER British Journal of Cancer (2013) 109, 280–288 | doi: 10.1038/bjc.2013.294 Keywords: non-Hodgkin’s lymphoma; Hodgkin’s lymphoma; transplantation; immunosuppression; Burkitt’s lymphoma; T-cell lymphoma Risk of lymphoma subtypes after solid organ transplantation in the United States ,1,2 3 4 3 3 3 5 C A Clarke , L M Morton , C Lynch , R M Pfeiffer , E C Hall , T M Gibson , D D Weisenburger , 6 6 1 2 3 O Martı´ nez-Maza , S K Hussain , J Yang , E T Chang and E A Engels 1 2 Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538-2334, USA; Division of Epidemiology, Department of Health Research and Policy and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA; 4 5 Department of Epidemiology, University of Iowa, Iowa City, IA, USA; Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA and Department of Epidemiology, University of California, Los Angeles, CA, USA Background: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. Methods: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. Results: The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt’s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (o20 years) and those receiving organs other than kidneys. Conclusion: Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma. Organ transplantation is a lifesaving option for individuals with most common malignancies diagnosed after transplant (Andreone end-stage organ disease, and over 28 000 solid organ transplanta- et al, 2003). Risk in transplant recipients is estimated as 3- to 21- tions are performed yearly in the United States. However, solid fold higher than that in the general population, and perhaps as organ transplant patients must receive intensive long-term much as 120-fold higher among children who receive transplants immunosuppressive therapy to prevent rejection of the transplant, (Kasiske et al, 2004; Busnach et al, 2006; Caillard et al, 2006; Vajdic putting them at high risk of developing post-transplant lympho- et al, 2006; Giordano et al, 2007; Grulich et al, 2007; Serraino et al, proliferative disorders (PTLDs). These disorders include a 2007; Jiang et al, 2008, 2010; Baccarani et al, 2009; Vajdic and van spectrum of potentially deadly lymphoid cell proliferations, Leeuwen, 2009; Quinlan et al, 2010; Engels et al, 2011). The NHL including non-Hodgkin lymphoma (NHL) and Hodgkin lym- risk exhibits a U-shaped pattern over time following transplanta- phoma (HL) (Tsao and Hsi, 2007). The NHL represents one of the tion, with risk being highest in the first year after transplant, falling *Correspondence: Dr CA Clarke; E-mail: tina@cpic.org Received 13 March 2013; revised 30 April 2013; accepted 20 May 2013; published online 11 June 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 280 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER subsequently, and then increasing again at 5 or more years from human subjects research approval at the Health after transplant (van Leeuwen et al, 2009; Quinlan et al, 2011). Resources and Services Administration and the North Carolina HL was once considered aetiologically distinct from NHL, cancer registry. but is now recognised as similar to some B-cell NHL Lymphoma outcomes and follow-up. The NHLs were identified subtypes. Risk of HL among transplant recipients is likely lower in transplant recipients through linkage with cancer registries. than that for NHL, having been reported as 2- to 3.6-fold higher Lymphoma subtypes were classified using International Classifi- than that in the general population (Quinlan et al, 2010; Engels cation of Diseases for Oncology, 3rd edition (ICD-O-3) site and et al, 2011). histology codes according to current International Lymphoma A major gap in our understanding of transplant-related Epidemiology (InterLymph) Consortium consensus guidelines lymphoma involves the spectrum and associated risks of the many (Turner et al, 2010). Transplant recipients were considered at risk histologic subtypes of lymphoma, which are heterogeneous with of lymphoma beginning at the date of transplantation or the start respect to clinical and epidemiologic characteristics (Morton et al, of cancer registry coverage (whichever came later). Hispanics were 2006; Swerdlow et al, 2008). The two prior studies examining the followed beginning in 1992 to correspond to the years for which risk of NHL subtypes among transplant recipients reported general population rates were available for comparison (see below). substantial elevation in the risk of diffuse large B-cell lymphoma Follow-up time ended at the first diagnosis of any lymphoma (DLBCL, the most common subtype in most populations) but no subtype, death, failure of a transplanted organ, subsequent increase for follicular lymphoma (another common subtype in transplant, loss to follow-up, or last date of cancer registry the general population) (Quinlan et al, 2010; Vajdic et al, 2010). coverage (whichever came first). Recipients were considered These studies were hampered by small numbers, especially of at risk separately during successive transplant episodes. Of the uncommon NHL subtypes, and did not examine how the 180 210 distinct transplant episodes, we excluded 1265 because occurrence of NHL subtypes varied by demographic characteristics racial/ethnic information was missing or did not correspond to a or time since transplantation. group for which general population cancer rates were available, Better characterisation of the risk of lymphoma subtypes in and a further 160 episodes occurring among recipients with human transplant recipients would help clinicians caring for these patients, immunodeficiency virus (HIV) infection reported to the SRTR. as different subtypes require different management. This infor- We did not exclude episodes if the recipient had a history of mation would also improve understanding of the causal impor- cancer before transplantation. Altogether, our final analytic cohort tance of immunosuppression. Therefore, we assessed the risks of included 178 785 transplant episodes occurring in 165 734 individual lymphoma subtypes in the recently completed Trans- individuals, 1617 NHL, and 48 HL cases. plant Cancer Match Study (Engels et al, 2011). This large cohort of Statistical analysis. For each lymphoma subtype, we measured the US solid organ transplant recipients, for whom cancer ascertain- ment was conducted uniformly via linkage with population-based risk in transplant recipients relative to the general population using the standardised incidence ratio (SIR, i.e., observed/expected cancer registries, enabled us to quantify the risks of specific subtypes overall and according to recipient age at transplantation, number of cases). Observed numbers were derived from the cancer registry linkages, as described above. Expected numbers type of transplanted organ, and time since transplant. were calculated by applying general population cancer incidence rates obtained from each cancer registry to person-time at risk among transplant recipients, stratified by sex, 5-year age group, MATERIALS AND METHODS race/ethnicity, and calendar year. Rates for whites, blacks, and Asians/Pacific Islanders were derived from participating registries. Transplant cancer match study. The Transplant Cancer Match Rates for Hispanics (available 1992 onward) were derived from the US Surveillance, Epidemiology, and End Results programme, in Study is described in detail elsewhere (http://transplantmatch. cancer.gov) (Engels et al, 2011). In brief, the US Scientific Registry which 8 of the 14 contributing cancer registries participate. The 95% confidence intervals (CIs) around each SIR were derived of Transplant Recipients (SRTR) was linked with 14 US population-based cancer registries. The SRTR includes structured assuming that the observed counts follow a Poisson distribution. We also calculated SIRs and 95% CIs across categories defined data regarding all US solid organ transplants occurring since 1987, including recipient demographic characteristics, reason for trans- by age at transplant, transplanted organ, and successive time intervals (1–360 days, 361–1800 days, and 1801þ days) plant, and characteristics of the transplanted organs. The cancer registries include standardised information regarding patient after transplant. Univariate Poisson regression models were created for each subtype and used to test for heterogeneity across these demographic characteristics and detailed tumour characteristics. Serial record linkages were completed between the SRTR and categories. the following central cancer registries, together covering B42% of In sensitivity analyses we (1) excluded all transplants for which the reported NHL was not the first haematologic malignancy the US transplant patient population: California (years of coverage: 1988–2008), Colorado (1988–2006), Connecticut (1973–2006), reported, and (2) excluded transplants for which there was a gap between date of transplant and the beginning of cancer registry Georgia (1995–2008), Hawaii (1973–2007), Illinois (1986–2007), Iowa (1973–2007), Michigan (1985–2006), New Jersey (1979– coverage. Results from these sensitivity analyses were similar to those from our main analysis and thus are not presented here. All 2006), New York (1976–2007), North Carolina (1990–2007), the Seattle-Puget Sound area of Washington State (1974–2008), CIs and statistical tests were two sided. Texas (1995–2006), and Utah (1973–2008). Record linkages were accomplished using a computer algorithm followed by manual RESULTS review and confirmation of potential matches. Analyses were restricted to transplant recipients residing in geographic areas covered by the cancer registries during the specified time periods. We evaluated 178 785 solid organ transplants in 165 734 individuals, The TCM Study was approved by human subjects research with 791 281 person-years of follow-up. Table 1 describes the review committees at the National Cancer Institute and the demographic characteristics of individuals who received these following cancer registries: California, Colorado, Connecticut, transplants. Of the transplant recipients, 61% were male, and the Georgia, Hawaii, Illinois, Iowa, Michigan, New Jersey, New York, median age at transplant was 47.0 years, with a quarter of patients Seattle-Puget Sound, Texas, and Utah. It was formally exempted under age 35 years at the time of transplant. Recipients were racially www.bjcancer.com | DOI:10.1038/bjc.2013.294 281 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation two-thirds of all post-transplant NHLs with specified subtype, and Table 1. Characteristics of 178,785 solid organ transplants*, United States, 1987–2008 for which the risk was over 13 times higher than in the general population (SIR¼ 13.5, 95% CI: 12.7–14.4). After DLBCL, the next most commonly diagnosed subtype was Burkitt’s lymphoma, Characteristic n (%) for which the risk was B25 times elevated (SIR¼ 24.5, 95% Sex CI: 19.6–30.2). Other B-cell lymphomas with significantly elevated risks included lymphoplasmacytic lymphoma (SIR¼ 2.8, 95% Male 108 805 (60.86) CI: 1.6–4.5) and marginal zone lymphoma of mucosa-associated Female 69 980 (39.14) lymphoid tissue (MALT; SIR¼ 2.8, 95% CI: 1.9–4.0). The risk of Age at transplant, years developing HL was significantly elevated 3.6-fold (SIR¼ 3.6, 95% CI: 2.9–4.4) compared with the general population. 0–19 16 130 ( 9.02) When T-cell lymphomas were considered as a single entity, the 20–34 28 128 (15.73) risk was seven-fold higher than in the general population 35–49 56 700 (31.71) (SIR¼ 7.1, 95% CI: 5.6–8.9; Table 2). Peripheral T-cell lymphomas 50–64 63 798 (35.68) and anaplastic large-cell lymphomas comprised over 80% of the 65þ 14 029 ( 7.85) T-cell lymphomas, with other subtypes occurring rarely. Race/ethnicity Among the T-cell lymphomas, the greatest risk elevation was for hepatosplenic T-cell lymphoma (SIR¼ 100, as noted above). White, non-Hispanic 109 702 (61.36) Other T-cell lymphomas with elevated risks included extranodal Black, non-Hispanic 29 868 (16.71) natural killer (NK)/T-cell lymphomas, nasal type (SIR¼ 15.0, 95% Hispanic 28 446 (15.91) CI: 6.5–29.6), anaplastic large-cell lymphoma (SIR¼ 12.8, 95% CI: Asian/Pacific Islander 10 769 ( 6.02) 9.0–17.7), primary cutaneous anaplastic large-cell lymphoma Transplanted organ (SIR¼ 13.5, 95% CI: 6.2–25.5), and other peripheral T-cell lymphomas (SIR¼ 3.9, 95% CI: 2.7–5). Kidney 104 466 (58.43) Among other specified NHLs, the risk was also elevated for Pancreas or kidney and pancreas 7 991 ( 4.47) precursor B- or T-cell lymphoblastic leukaemia/lymphoma, Liver 38 473 (21.52) compared with the general population (SIR¼ 2.0, 95% Heart and/or lung 25 449 (14.23) CI: 1.23–3.20). In sharp contrast, few cases and no significant Other or multiple 2406 ( 1.35) elevations in risk were observed for follicular lymphoma, Transplant number small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL/SLL), mantle cell lymphoma, or mycosis fungoides/Se´zary’s First 163 071 (91.21) syndrome. Second 14 404 ( 8.06) The risks differed substantially according to the age at Third or higher 1310 ( 0.73) transplant, with a strong inverse relationship between SIRs and age demonstrated for several NHL subtypes and HL (Table 3). Calendar year of transplant Among recipients aged o20 years at the time of trans- 1987–1994 35 280 (19.73) plantation, the risks were strikingly elevated for Burkitt’s 1995–1999 46 890 (26.23) lymphoma (SIR¼ 123, 95% CI: 79.0–183), DLBCL (SIR¼ 379, 2000–2004 57 801 (32.33) 95% CI: 318–447), peripheral T-cell lymphoma (SIR¼ 172, 95% 2005–2008 38 814 (21.71) CI: 69.1–354), and anaplastic large-cell lymphoma (SIR¼ 96.9, 95% CI: 41.8–191). For many subtypes, it was difficult to assess *Includes 178,785 solid organ transplant episodes occurring in 165,734 recipients. gradients in risk by age because there were fewer than three cases diagnosed among those aged o20 years at transplant. Notably, and ethnically diverse, with almost 40% of patients being non-white. however, the risks for most subtypes among individuals aged Z50 Kidney transplants were most common, but 41% of transplants were years at the time of transplantation remained elevated compared of other organs, and 91% were first transplants. with the general population. Through matches with cancer registry records, 1617 NHL Table 4 shows that for some subtypes, the patterns of risk also diagnoses and 48 HL diagnoses among transplant recipients were differed with respect to time since transplant, although for other identified. Of the NHLs, specific histologic subtype was reported subtypes, the numbers were small and differences were not for 1285 (80%). Compared with cases with specified subtypes, significant. The SIRs for DLBCL and anaplastic large-cell NHLs for which histologic subtype was not reported (i.e., ‘NHL, lymphoma showed a U-shaped pattern, with risks highest in the not otherwise specified’) were similar in terms of age, sex, and first year after transplant, lower at 361–1800 days after transplant, organ transplanted, but were significantly (Po0.05) more likely to and slightly higher again 1801þ days after transplant. In contrast, have disease limited to lymph nodes (i.e., nodal) and to have been SIRs for HL, Burkitt’s lymphoma, peripheral T-cell lymphomas, diagnosed in the earlier years of the study (e.g., 1987–1994). and hepatosplenic T-cell lymphoma were not statistically signi- Overall, transplant recipients had over six-fold increased risk of ficantly elevated in the first year after transplant but increased developing any kind of NHL compared with the general population subsequently, with markedly elevated relative risk observed 1801þ (SIR¼ 6.2, 95% CI: 5.9–6.5). Table 2 describes the risk for 19 days after transplant. defined distinct NHL subtypes. Among NHLs for which specific The risk of lymphoma subtypes differed by the type of organ subtypes were reported, 85.5% were B-cell lymphomas and 6.2% transplanted (Table 5). For most subtypes, kidney recipients had were T-cell lymphomas. The NHL subtype with the highest lower SIRs than liver or thoracic organ (heart and/or lung) elevation in risk was hepatosplenic T-cell lymphoma, an recipients (although still elevated compared with the general uncommon NHL subtype for which the risk was elevated 100- population in many instances). However, the number of cases for fold (SIR¼ 100, 95% CI: 33–234) above the general population. many subtypes was small, and risk did not differ significantly by However, this increase was based on only six cases and an organ. The risks for DLBCL and anaplastic large-cell lymphoma incidence rate of less than one per 100 000 person-years. The most were highest among pancreas and kidney/pancreas recipients, common subtype diagnosed was DLBCL, which comprised almost whereas Burkitt’s lymphoma risk was highest among liver and 282 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER Table 2. Overall SIRs for lymphoma subtypes among solid organ transplant recipients, United States, 1987–2008 Incidence rate / Observed 100 000 ICD-O-3 site and histology codes count SIR 95% CI person-years B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 9687, 9826 88 24.5 19.7–30.2 11.1 Chronic lymphocytic lymphoma/ 9670, 9823 36 0.7 0.5–0.9 4.5 small lymphocytic lymphoma Diffuse large B-cell lymphoma 9678–9680, 9684 948 13.5 12.7–14.4 119.8 Follicular lymphoma 9690, 9691, 9695, 9698 38 0.9 0.7–1.3 4.8 Lymphoplasmacytic lymphoma 9671, 9761 16 2.8 1.6–4.5 2.0 Mantle cell 9673 3 0.4 0.1–1.0 0.4 Marginal zone 9689, 9699, 9760, 9764, 9699, 9715 35 2.2 1.6–3.1 4.4 Splenic/nodal marginal zone 9689, 9699 (site 77.0–77.9), 9715 (site 77.0–77.9) 6 1.1 0.4–2.4 0.8 MALT type 9760, 9764, 9699 (excl site 77.0–77.9), 9715 (excl site 77.0–77.9) 29 2.8 1.9–4.0 3.7 T-cell lymphoma subtype Peripheral T-cell lymphoma 9702, 9705, 9708, 9709, 9717 30 3.9 2.7–5.6 3.8 ALCL 9714 36 12.8 9.0–17.7 4.5 Primary cutaneous ALCL 9718 9 13.5 6.2–25.5 1.1 Mycosis fungoides/Se´ zary’s 9700, 9701 8 1.6 0.7–3.2 1.0 syndrome Hepatosplenic T-cell lymphoma 9716 5 100 33–234 0.6 NK/T-cell lymphoma 9719 8 15.0 6.5–29.6 1.0 All T-cell lymphoma combined 9702–9718 80 7.1 5.7–8.9 10.1 Precursor B- or T-cell 9727–9729, 9835–9837 19 2.0 1.2–3.2 2.4 lymphoblastic leukaemia/lymphoma NHL, other 9762, 9827, 9831–9834, 9940, 9948 9 1.7 0.8–3.3 1.1 NHL, not otherwise specified 9590–9595, 9675, 9820, 9970 332 10.2 9.1–11.3 42.0 All NHL 9590–9595, 9670, 9671, 9673, 9675, 9678–9680, 9684, 9687, 1617 6.2 5.9–6.5 204.4 9689, 9690, 9691, 9695, 9698, 9699, 9700, 9701, 9702, 9705, 9708, 9709, 9714, 9715, 9716, 9717, 9718, 9719, 9727–9729, 9760, 9761, 9762, 9764, 9820, 9823, 9826, 9827, 9831–9837, 9940, 9948, 9970 Hodgkin’s lymphoma (excluding nodular lymphocyte 9650–9655, 9661–9665, 9667 83 3.6 2.9–4.4 10.5 predominant type) Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; ICD-O-3¼ International Classification of Diseases for Oncology, 3rd edition; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio. Bold indicates SIRs significantly different from 1 at Po0.05. thoracic organ recipients. None of the recipients who developed and anaplastic large-cell lymphoma (both systemic and primary hepatosplenic T-cell lymphoma received a liver transplant, rather, cutaneous forms). For DLBCL and Burkitt’s lymphoma, which four of the six recipients received kidneys. were the most common lymphoma subtypes after transplant, the The patterns for NHL overall according to age, organ type, and relative risks were most strongly pronounced among transplant time since transplant generally mirrored those observed for patients under age 20 years, and differed according to the type DLBCL, the most common subtype (Tables 3–5). Similarly, the of organ transplanted. We also observed moderately elevated patterns of risk of unclassified lymphoma (NHL, not otherwise risks (i.e., 2- to 3-fold higher than the general population) for HL, specified) were also similar to those observed for DLBCL. lymphoplasmacytic lymphomas, precursor B- or T-cell lympho- blastic leukaemia/lymphoma, other T-cell lymphomas, and marginal zone lymphoma of MALT type, whereas the risks were not increased for follicular or mantle cell lymphomas, CLL/SLL, or DISCUSSION mycosis fungoides/Sezary’s syndrome. The mechanisms explaining the different spectrum of Non-Hodgkin’s lymphoma is among the most common malig- lymphoma subtypes among transplant patients compared with nancies diagnosed among solid organ transplant recipients. the general population include immunosuppression, including the Overall, the risk for NHL is six-fold higher following transplanta- early, intense induction phase and the later maintenance phase; tion than in the general population, but in this large, population- chronic immune activation because of the presence of donor organ based study we demonstrate that the risks vary dramatically tissue; or the combined effects of these, resulting in long-term, by lymphoma subtype. Elevated risks were particularly striking chronic immune dysfunction. The lymphoma subtypes for which (410-fold) for hepatosplenic T-cell lymphoma, Burkitt’s the risk is elevated are similar to those that are increased in lymphoma, extranodal NK/T-cell lymphoma nasal type, DLBCL, HIV-infected patients (Mbulaiteye et al, 2003; Biggar et al, 2007; www.bjcancer.com | DOI:10.1038/bjc.2013.294 283 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation Table 3. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by age at transplant year, United States, 1987–2008 Age at transplant year 0–19 20–34 35–49 50–64 65þ Poisson 95% 95% 95% 95% 95% Subtype n SIR CI n SIR CI n SIR CI n SIR CI n SIR CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 24 123 79–183 16 39.7 22.7–64.4 21 17.7 10.9–27.0 24 16.7 10.7–24.9 3 8.1 1.7–23.8 o0.0001 Chronic lymphocytic lymphoma /small o3 77.2 2.0–430.2 o3 2.4 0.1–13.6 5 0.6 0.2–1.5 23 0.7 0.4–1.0 6 0.5 0.2–1.0 0.05 lymphocytic lymphoma Diffuse large B-cell lymphoma 138 379 318–447 135 40.3 33.8–47.7 249 15.6 13.7–17.6 348 9.4 8.4–10.5 78 5.8 4.6–7.3 o0.0001 Follicular lymphoma o3 36.6 4.4–132 4 3.4 0.9–8.8 8 0.8 0.4–1.6 20 0.9 0.5–1.4 4 0.6 0.2–1.6 0.0025 Lymphoplasmacytic lymphoma 0 0.0 0–1124 0 0.0 0.0–55.9 3 3.5 0.7–10.3 8 2.4 1.0–4.7 5 3.5 1.1–8.1 0.91 Mantle cell 0 0.0 0–2583 0 0.0 0.0–52.4 0 0.0 0.0–2.7 o3 0.4 0.1–1.4 o3 0.5 0.0–3.1 – Marginal zone 0 0.0 0–111 5 12.8 4.2–29.9 13 4.1 2.2–7.1 9 1.0 0.5–1.9 8 2.5 1.1–4.9 0.0003 Splenic/nodal marginal zone 0 0.0 0–463 3 30.7 6.3–89.8 o3 1.0 0.0–5.7 o3 0.3 0.0–1.8 o3 0.8 0.0–4.7 0.0022 MALT type 0 0.0 0–147 o3 6.8 0.8–24.7 12 5.5 2.9–9.7 8 1.4 0.6–2.7 7 3.5 1.4–7.1 0.02 T-cell lymphoma subtype Peripheral T-cell lymphoma 7 172 69–354 4 12.9 3.5–33.1 6 3.5 1.3–7.7 9 2.1 1.0–4.1 4 2.9 0.8–7.5 o0.0001 ALCL 8 96.9 41.8–191 6 27.7 10.2–60.4 8 10.8 4.7–21.4 14 10.1 5.5–17.0 0 0.0 0.0–9.3 o0.0001 Primary cutaneous ALCL o3 127 3–706 0 0.0 0.0–114.6 o3 12.7 1.5–45.9 4 11.2 3.1–28.7 o3 17.5 2.1–63.4 0.43 Mycosis fungoides/ Se´ zary’s syndrome o3 33.3 0.8–185 0 0.0 0.0–14.2 4 3.1 0.8–7.9 o3 0.8 0.1–2.8 o3 1.4 0.0–7.6 0.10 Hepatosplenic T-cell lymphoma o3 269 7–1501 0 0.0 0.0–387.7 o3 109 13–393 o3 131 16–472 0 0.0 0.0–1256.2 0.50 NK/TCL, nasal type 0 0.0 0–316.0 o3 17.4 0.4–96.9 o3 6.2 0.2–34.6 6 25.9 9.5–56.5 0 0.0 0.0–52.2 0.28 All T-cell lymphoma 17 126 73–202 10 17.5 8.4–32.2 18 6.8 4.0–10.8 29 4.8 3.2–6.9 6 3.2 1.2–6.9 o0.0001 Precursor B- or T- cell lymphoblastic 7 3.2 1.3–6.6 3 3.0 0.6–8.6 4 1.9 0.5–4.8 5 1.6 0.5–3.7 0 0.0 0.0–4.8 0.27 leukaemia/lymphoma NHL, other o3 79.0 2.0–440 o3 4.9 0.1–27.5 3 2.0 0.4–5.9 4 1.4 0.4–3.7 0 0.0 0.0–4.8 0.05 NHL, not otherwise specified 39 266 189–363 40 26.3 18.8–35.8 93 13.0 10.5–15.9 132 7.6 6.4–9.0 28 4.4 2.9–6.4 o0.0001 All NHL 230 72.1 63.1–82.1 216 22.8 19.9–26.1 422 7.7 7.0–8.5 609 4.2 3.9–4.6 140 2.8 2.4–3.3 o0.0001 Hodgkin’s lymphoma 20 14.1 8.6–21.8 16 3.6 2.0–5.8 21 3.0 1.9–4.6 24 2.9 1.9–4.3 o3 1.0 0.1–3.5 o0.0001 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. ‘–’ Indicates too few cases to estimate heterogeneity. Bold indicates SIRs significantly different from 1 at Po0.05. Engels et al, 2008; Vajdic et al, 2010), another population EBV seronegative at transplantation, which puts them at risk of experiencing both chronic immunosuppression and immune subsequent primary EBV infection and PTLD (Jenson, 2011; activation. Investigators in the United States and Australia have Quinlan et al, 2011). For Burkitt’s lymphoma, which is also an demonstrated especially elevated risks among HIV-infected aggressive lymphoma, the risk was similarly highest in children, individuals for ‘high-grade’ NHL subtypes as a group (SIR B50– but was not elevated in the first year after transplant and rose with 110) and for DLBCL (SIRs 25–100), Burkitt’s lymphoma (SIRs 50– time since transplant. Of interest, only 40–60% of HIV-associated 140), and T-cell lymphomas (SIR B15) (Mbulaiteye et al, 2003; Burkitt’s lymphoma is EBV related (Carbone et al, 2009). We were Engels et al, 2006; van Leeuwen et al, 2009; Vajdic et al, 2010). In unable to separate EBV-defined cases, and it is possible that the age contrast, follicular or ‘low-grade’ lymphoma risks were not higher and latency patterns that we observed reflect mixed occurrence for than in the general population in any of the transplant or HIV- EBV-positive and -negative forms of Burkitt’s lymphoma after infected groups (Mbulaiteye et al, 2003; Quinlan et al, 2010; Vajdic transplant (Carbone et al, 2009). Transplant-related cases of HL et al, 2010). The overall relative risks observed here are lower than are also commonly EBV positive (Bierman et al, 1996; Knight et al, those observed in HIV-infected populations, perhaps because of 2009), and in our study, HL risk also increased with time since the different pattern of immunosuppression or the different type of transplant. immune stimulus conferred by a donor organ than associated with We also observed statistically significantly elevated risks of HIV infection. marginal zone lymphomas of MALT type and lymphoplasmacytic These data are informative with regard to several aspects of lymphoma, although the magnitudes of elevation were lower than lymphomagenesis for specific subtypes. For DLBCL, our observa- those for DLBCL and Burkitt’s lymphoma. Outside of the tions are consistent with the known role of Epstein–Barr virus transplant setting, these subtypes are thought to arise under (EBV)-driven B-cell expansion under conditions of intense conditions of persistent immune stimulation by chronic microbial immunosuppression, especially in children. Epstein–Barr virus is infections (e.g., Helicobacter pylori for gastric MALT type detected in the tumour cells of most transplant-related DLBCLs lymphoma, hepatitis C virus for lymphoplasmacytic lymphoma) (Carbone et al, 2009). We found that the risk of developing DLBCL (Engels, 2007; Giordano et al, 2007; de Sanjose et al, 2008). was concentrated in children (ages 0–19 years), and was highest in Transplant-related immunosuppression may increase microbial the first year after transplant. These findings agree with previous activity or modulate the immune response against these micro- reports of transplant-related NHL overall and PTLD (Opelz et al, organisms. In contrast, for other indolent B-cell lymphomas such 2009; Vajdic and van Leeuwen, 2009) and are expected, given that as follicular lymphoma and CLL/SLL, our data are not suggestive of DLBCL comprises a large fraction of PTLD. Children are often major roles for the types of immunosuppression, immune 284 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER Table 4. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by time since transplant, United States, 1987–2008 Time since transplant 1–360 days 361–1800 days 1801þ days Poisson Subtype n SIR 95% CI n SIR 95% CI n SIR 95% CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia o3 3.3 0.4–11.8 54 31.7 23.8–41.3 32 25.0 17.1–35.3 o0.0001 Chronic lymphocytic lymphoma/small 11 1.4 0.7–2.4 12 0.5 0.3–0.9 13 0.6 0.3–1.0 0.05 lymphocytic lymphoma Diffuse large B-cell lymphoma 335 30.1 26.9–33.5 305 9.4 8.4–10.5 308 11.6 10.4–13.0 o0.0001 Follicular lymphoma 13 2.1 1.1–3.5 8 0.4 0.2–0.9 17 1.1 0.6–1.8 0.0014 Lymphoplasmacytic lymphoma 3 3.5 0.7–10.4 6 2.3 0.9–5.1 7 3.0 1.2–6.2 0.81 Mantle cell o3 0.8 0.0–4.7 o3 0.3 0.0–1.5 o3 0.3 0.0–1.6 0.71 Marginal zone 6 2.7 1.0–5.9 13 1.9 1.0–3.2 16 2.4 1.4–3.9 0.69 Splenic/nodal marginal zone o3 1.3 0.0–7.5 o3 0.4 0.0–2.4 4 1.7 0.5–4.4 0.38 MALT type 5 3.4 1.1–7.9 12 2.6 1.4–4.6 12 2.8 1.5–4.9 0.89 T-cell lymphoma subtype Peripheral T-cell lymphoma o3 1.7 0.2–6.2 11 3.2 1.6–5.7 17 5.7 3.3–9.1 0.11 ALCL 15 32.8 18.4–54.1 5 3.7 1.2–8.7 16 15.6 8.9–25.4 o0.0001 Primary cutaneous ALCL 3 32.4 6.7–94.7 o3 3.5 0.1–19.6 5 17.1 5.6–40.0 0.08 Mycosis fungoides/Se´ zary’s syndrome o3 2.4 0.3–8.7 o3 0.8 0.1–3.1 4 2.3 0.6–5.8 0.42 Hepatosplenic T-cell lymphoma 0 0.0 0.0–451.4 o3 42.7 1.1–238.0 4 219 60–560 0.10 NK/TCL, nasal type o3 11.9 0.3–66.33 3 12.3 2.6–36.1 4 19.4 5.3–48.6 0.81 All T-cell lymphoma 20 11.5 7.0–17.8 18 3.5 2.1–5.5 42 9.7 7.0–13.1 o0.0001 Precursor B- or T-cell lymphoblastic o3 1.2 0.1–4.2 11 2.4 1.2–4.3 6 2.0 0.7–4.3 0.59 leukaemia/lymphoma NHL, other 0 0.0 0.0–4.3 5 2.0 0.7–4.7 4 2.1 0.6–5.4 0.20 NHL, not otherwise specified 115 20.2 16.7–24.3 124 7.8 6.5–9.3 93 8.4 6.8–10.3 o0.0001 All NHL 511 12.4 11.3–13.5 561 4.6 4.3–5.0 545 5.5 5.0–6.0 o0.0001 Hodgkin’s lymphoma 6 1.4 0.5–3.1 36 3.2 2.2–4.4 41 5.4 3.9–7.3 0.001 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. Bold indicates SIRs significantly different from 1 at Po0.05. activation, or other immune disturbances experienced by trans- young transplant recipients. This pattern probably reflects the plant recipients. contribution of primary EBV infection in younger recipients, as Although T-cell lymphomas constituted a small proportion of well as a countervailing age-related rise in NHL incidence in the NHLs in this transplant population, we observed very high relative general population due to other mechanisms. Although we risks of certain T-cell subtypes, including hepatosplenic T-cell confirmed a U-shaped pattern in overall NHL risk over time, a lymphoma and both systemic and primary cutaneous anaplastic pattern previously observed by others (van Leeuwen et al, 2009; large-cell lymphomas. For anaplastic large-cell lymphoma, relative Quinlan et al, 2011), we did not find a consistent pattern of risk risks were markedly elevated in the first year after transplant. Of across all the specific subtypes. Intense, T cell-depleting induction interest, EBV is not generally thought to play an important role in immunosuppressive agents used at the time of transplantation may the aetiology of T-cell PTLD (Engels, 2007). Although the explain why the relative risks of DLBCL and systemic and exceedingly rare hepatosplenic T-cell lymphoma is well recognised cutaneous anaplastic large-cell lymphoma were highest nearer the as a type of PTLD, EBV is infrequently detected in tumour cells of time of transplant. In contrast, the relative risk of Burkitt’s this malignancy (Engels, 2007). The very high relative risks of lymphoma increased with longer time since transplant. Among hepatosplenic T-cell and anaplastic large-cell lymphomas observed older recipients and among recipients many years post transplant, here after transplant, but not in HIV-infected individuals lymphoma occurrence may be caused by some combination of age- (Opelz and Dohler, 2004; LaCasce, 2006), may suggest that unique related immune senescence, immunosuppression-related immune aspects of transplant-associated immune disturbance are aetiolo- dysfunction, and chronic antigenic stimulation from the trans- gically important. Inflammatory and anti-inflammatory activity are planted graft or infection (Opelz and Dohler, 2004; Vajdic and van of interest because of the apparent association of hepatosplenic Leeuwen, 2009; van Leeuwen et al, 2009). T-cell lymphomas with use of tumour necrosis factor-a (TNF-a) Our analysis is the first to assess lymphoma subtype occurrence inhibitors for Crohn’s disease, arthritis, and other autoimmune by the type of organ transplanted. The relative risk of DLBCL was diseases (Hellgren et al, 2010; Deepak et al, 2013; Mason and substantially higher among pancreas and pancreas/kidney recipi- Siegel, 2013). It is also interesting that none of the hepatosplenic ents than recipients of other organs, and Burkitt’s lymphoma risk T-cell lymphomas occurred in liver recipients, among whom the was highest among recipients of liver and thoracic organ (heart donor organ provides a strong and sustained local immune and/or lung) transplants. Most prior studies of post-transplant stimulus. cancer risk have focussed on kidney recipients, but some have Our data also demonstrate substantial variation in the risk of reported higher risks of overall NHL for small intestine or lung lymphoma subtypes according to age and time since transplant. In recipients than heart, liver, or kidney recipients (LaCasce, 2006; general, SIRs for most lymphoma subtypes were elevated among Tsao and Hsi, 2007). In the Collaborative Transplant Study, PTLD www.bjcancer.com | DOI:10.1038/bjc.2013.294 285 BRITISH JOURNAL OF CANCER Lymphoma subtypes after transplantation Table 5. SIRs and 95% CIs for development of lymphoma subtypes in subgroups of solid organ transplant recipients by transplanted organ, United States, 1987–2008 Transplanted organ Pancreas or kidney and Heart Kidney pancreas Liver and/or lung Other or multiple Poisson 95% 95% 95% 95% 95% Subtype n SIR CI n SIR CI n SIR CI n SIR CI n SIR CI P-value* B-cell lymphoma subtype Burkitt’s lymphoma/leukaemia 29 14.4 9.7–20.7 o3 7.4 0.2–41.1 38 47.1 33.3–64.6 20 33.0 20.2–51.0 0 0.0 0.0–116.0 o0.0001 Chronic lymphocytic lymphoma/small 18 0.7 0.4–1.1 0 0.0 0.0–4.4 10 0.8 0.4–1.5 8 0.6 0.3–1.2 0 0.0 0.0–8.5 0.73 lymphocytic lymphoma Diffuse large B-cell lymphoma 411 11.0 9.9–12.1 55 32.6 24.6–42.5 215 13.1 11.4–15.0 254 18.2 16.0–20.6 13 22.5 12.0–38.5 o0.0001 Follicular lymphoma 17 0.8 0.5–1.3 0 0.0 0.0–3.5 15 1.5 0.8–2.5 6 0.7 0.3–1.6 0 0.0 0.0–10.6 0.18 Lymphoplasmacytic lymphoma 10 3.5 1.7–6.4 0 0.0 0.0–42.4 o3 0.7 0.0–4.1 5 3.7 1.2–8.6 0 0.0 0.0–79.4 0.34 Mantle cell o3 0.5 0.1–1.8 0 0.0 0.0–24.1 o3 0.5 0.0–2.7 0 0.0 0.0–1.8 0 0.0 0.0–49.0 0.76 Marginal zone 16 1.9 1.1–3.1 o3 3.0 0.1–16.6 12 3.1 1.6–5.4 5 1.7 0.5–3.9 o3 7.2 0.2–40.1 0.54 Splenic/nodal marginal zone 4 1.4 0.4–3.6 0 0.0 0.0–34.6 0 0.0 0.0–2.7 o3 1.8 0.2–6.5 0 0.0 0.0–73.5 0.41 MALT type 12 2.2 1.1–3.8 o3 4.4 0.1–24.4 12 4.8 2.5–8.4 3 1.6 0.3–4.6 o3 11.3 0.3–62.7 0.16 T-cell lymphoma subtype Peripheral T-cell lymphoma 15 3.6 2.0–5.9 o3 5.7 0.1–31.7 8 4.7 2.0–9.3 6 4.1 1.5–8.9 0 0.0 0.0–55.8 0.90 ALCL 14 9.2 5.0–15.4 o3 24.0 2.9–86.7 9 14.4 6.6–27.3 10 18.1 8.7–33.2 o3 42.9 1.1–239.2 0.33 Primary cutaneous ALCL 4 11.3 3.1–28.9 0 0.0 0.0–190.2 3 19.2 4.0–56.1 o3 15.1 1.8–54.4 0 0.0 0.0–572.4 0.88 Mycosis fungoides/Se´ zary’s syndrome o3 0.7 0.1–2.6 o3 8.2 0.2–45.7 3 2.8 0.6–8.2 o3 2.0 0.3–7.4 0 0.0 0.0–93.1 0.37 Hepatosplenic T-cell lymphoma 4 131 36–334 0 0.0 0.0– o3 109 3–608 0 0.0 0.0–481.6 0 0.0 0.0– – 1753.0 12027.9 NK/TCL, nasal type 6 19.5 7.1–42.4 0 0.0 0.0–216.0 0 0.0 0.0–31.2 o3 23.9 2.9–86.3 0 0.0 0.0–725.5 – All T-cell lymphoma 37 6.0 4.2–8.3 3 10.6 2.2–31.1 21 8.4 5.2–12.8 18 8.2 4.9–13.0 o3 10.4 0.3–57.7 0.63 Precursor B- or T-cell lymphoblastic leukaemia/ 7 1.4 0.6–3.0 0 0.0 0.0–14.3 7 2.9 1.2–6.0 4 2.4 0.7–6.3 o3 8.8 0.2–49.0 0.36 lymphoma NHL, other 4 1.5 0.4–3.8 o3 6.2 0.2–34.7 o3 0.8 0.0–4.6 3 2.7 0.6–7.8 0 0.0 0.0–84.1 0.64 NHL, not otherwise specified 126 7.3 6.1–8.7 22 32.0 20.1–48.5 76 10.3 8.1–12.8 102 14.6 11.9–17.7 6 25.8 9.5–56.2 o0.0001 All NHL 684 5.0 4.6–5.4 84 14.4 11.5–17.9 398 6.4 5.8–7.1 429 7.7 7.0–8.5 22 10.1 6.3–15.3 o0.0001 Hodgkin’s lymphoma 48 3.6 2.6–4.7 o3 2.0 0.2–7.2 14 3.0 1.6–5.0 18 4.7 2.8–7.4 o3 5.5 0.1–30.9 0.61 Abbreviations: ALCL¼ anaplastic large-cell lymphoma; CI¼ confidence interval; MALT¼ mucosa-associated lymphoid tissue; NHL¼ non-Hodgkin’s lymphoma; NK¼ natural killer; SIR¼ standardised incidence ratio; TCL¼ T-cell lymphoma. *P-value from univariate Poisson regression testing for heterogeneity across categories. ‘–’ Indicates too few cases to estimate heterogeneity. risk was substantially higher among heart/lung and lung recipients 2012) and, moreover, suggest a specific range of lymphoma than among other recipients (Opelz and Dohler, 2004). Variation subtypes as differential diagnoses among such patients. Correct in the risk of DLBCL and other subtypes by organ type may relate diagnosis of subtype is important for management of post- to differences in immunosuppressive regimens or the intensity of transplant lymphoma, most importantly for planning therapeutic immunosuppression. Along these lines, some studies have shown regimen, which varies substantially by specific lymphoma subtype. that overall NHL risk is higher with certain induction immuno- This study has several important strengths. It is the first cohort suppression agents, particularly monoclonal anti-CD3 antibody study of transplant recipients to have a large enough number of (Bustami et al, 2004; Dharnidharka et al, 2012). Among HIV- incident lymphoma cases to allow assessing risks separately for a infected patients, the risk of DLBCL also has been shown to wide spectrum of subtypes. Prior efforts to quantify these risks correlate with the degree of immunosuppression as reflected by have been limited by lack of data on lymphoma subtypes, or small CD4 count (Biggar et al, 2007). Alternatively, it is possible that size and restriction to special subgroups of transplant patients, for different transplanted organs confer different levels of chronic example, kidney recipients (Vajdic et al, 2010) or Medicare antigen stimulation relevant to lymphomagenesis. beneficiaries over age 65 years (Quinlan et al, 2010). Our cohort Although DLBCL is the most commonly diagnosed B-cell included a well-defined, population-based sample of the US malignancy in the general population, it represents only 25–30% of transplant population, and linkage with corresponding popula- all NHL cases (Morton et al, 2006), whereas it comprises over half tion-based cancer registries allowed for highly complete, uniform of all transplant-related NHLs. Follicular lymphoma and CLL/SLL cancer ascertainment. each comprise B15–20% of NHLs diagnosed in the general Among the study’s limitations, we note that lymphoma subtype population, but o3% of NHL cases in our transplant cohort. classifications were derived from cancer registry abstractions of Notably, transplant recipients thus have higher proportions of medical records, which may not have been standard and may have aggressive subtypes and lower proportions of indolent B-cell been affected by changes in lymphoma diagnostic practice over lymphomas. Because many of the subtypes with elevated risk are time. Our prior studies of cancer registry classification of rare in the general population, our results underscore the lymphoma subtypes suggest good reliability for some subtypes importance of expert haematopathologic workup of suspicious (e.g., DLBCL, follicular lymphoma) (Clarke et al, 2004, 2006). lymphoproliferations among transplant patients (Jagadeesh et al, However, misclassification would be more likely for less common 286 www.bjcancer.com | DOI:10.1038/bjc.2013.294 Lymphoma subtypes after transplantation BRITISH JOURNAL OF CANCER NHL subtypes and for cases diagnosed in the earlier years of this Cancer Research Center in Seattle, WA. We gratefully acknowledge study before widespread dissemination of the international the support and assistance provided by individuals at the Health consensus guidelines (Clarke et al, 2004, 2006). In addition, we Resources and Services Administration (including Monica Lin), the could not examine risks across the full spectrum of PTLDs, because SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), US cancer registries collect information only for cases deemed and the following cancer registries: the states of California malignant by a pathologist. Despite the large number of NHL (Christina Clarke), Colorado (Jack Finch), Connecticut (Lou cases, we did not have adequate numbers of rare subtypes, Gonsalves), Florida (Brad Wohler), Georgia (Rana Bayakly), including most T-cell lymphomas, to reliably assess risk according Hawaii (Marc Goodman), Iowa (Charles Lynch), Illinois (Lori to age or time since transplant. We note that our estimated risk for Koch), Michigan (Glenn Copeland), New Jersey (Karen Pawlish, overall NHL included CLL, which is now understood to be the Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika same entity as SLL (Turner et al, 2010). Inclusion of CLL/SLL Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the decreased the SIR for overall NHL, which affects comparisons with Seattle-Puget Sound area of Washington (Margaret Madeleine). previous reports (Kasiske et al, 2004; Caillard et al, 2006; Vajdic We also thank analysts at Information Management Services for et al, 2006; Giordano et al, 2007; Serraino et al, 2007; Jiang et al, programming support (David Castenson, Ruth Parsons). 2008, 2010; Baccarani et al, 2009; Quinlan et al, 2010; Engels et al, 2011). Finally, we lacked information on tumour EBV status, and CONFLICT OF INTEREST hence we could not separately examine the risk for EBV-defined lymphoma subtypes. In conclusion, we found substantial differences in the risk for The authors declare no conflict of interest. individual lymphoma subtypes and varying patterns in association with age, transplanted organ, and time since transplantation. These results highlight that NHL should not be considered a single entity DISCLAIMER in studies of lymphoid malignancy or PTLD after transplant. There is a characteristic clinical spectrum of NHL subtypes among The ideas and opinions expressed herein are those of the authors transplant recipients. Because lymphoma treatment varies by and endorsement by the National Cancer Institute, Health subtype, patients suspected of having lymphoma should receive a Resources and Services Administration, SRTR, the Centers for detailed haematopathologic workup. Our findings also provide new Disease Control and Prevention, and individual state cancer insight into the importance of immunosuppression for the registries or their Contractors and Subcontractors is not intended development of some lymphoma subtypes. 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After 12 months the work will become freely available and Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA (2003) Immune deficiency the license terms will switch to a Creative Commons Attribution- and risk for malignancy among persons with AIDS. J Acquir Immune Defic NonCommercial-Share Alike 3.0 Unported License. Syndr 32: 527–533. 288 www.bjcancer.com | DOI:10.1038/bjc.2013.294

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Published: Jun 11, 2013

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