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J Clin Oncol. 2010 November 20; 28(33): 4935–4944.
Published online 2010 October 12. doi:  10.1200/JCO.2010.29.1112
PMCID: PMC3020697

Second Malignancy Risks After Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: Differences by Lymphoma Subtype

Abstract

Purpose

Previous studies have shown increased risks of second malignancies after non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype.

Patients and Methods

We evaluated second cancer and leukemia risks among 43,145 1-year survivors of CLL/small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL) from 11 Surveillance, Epidemiology, and End Results (SEER) population-based registries during 1992 to 2006.

Results

Among patients without HIV/AIDS–related lymphoma, lung cancer risks were significantly elevated after CLL/SLL and FL but not after DLBCL (standardized incidence ratio [SIR], CLL/SLL = 1.42, FL = 1.28, DLBCL = 1.00; Poisson regression P for difference among subtypes, PDiff = .001). A similar pattern was observed for risk of cutaneous melanoma (SIR: CLL/SLL = 1.92, FL = 1.60, DLBCL = 1.06; PDiff = .004). Acute nonlymphocytic leukemia risks were significantly elevated after FL and DLBCL, particularly among patients receiving initial chemotherapy, but not after CLL/SLL (SIR: CLL/SLL = 1.13, FL = 5.96, DLBCL = 4.96; PDiff < .001). Patients with HIV/AIDS–related lymphoma (n = 932) were predominantly diagnosed with DLBCL and had significantly and substantially elevated risks for second anal cancer (SIR = 120.50) and Kaposi's sarcoma (SIR = 138.90).

Conclusion

Our findings suggest that differing immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibilities, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes contribute to the patterns of second malignancy risk. Elucidating these patterns may provide etiologic clues to lymphoma as well as to the second malignancies.

INTRODUCTION

Non-Hodgkin's lymphomas (NHLs) are closely related yet heterogeneous diseases distinguished by specific morphologic, immunophenotypic, genetic, and clinical features.1 Some NHLs are potentially curable with chemotherapy and, less often, radiotherapy; however, treatment protocols vary by NHL subtype and continue to evolve.2 In addition, the clinical course and survival after NHL diagnosis vary among subtypes, with the 5-year relative survival for the major NHL subtypes ranging from 52% for the aggressive diffuse, large B-cell lymphoma (DLBCL) to approximately 75% for the more indolent follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).3 Evidence increasingly supports some etiologic heterogeneity among NHL subtypes as well, with particularly notable differences in risk for infectious agents, autoimmune diseases, and genetic susceptibility.49

Previous studies have shown increased risks of second malignancies after NHL1022 and CLL,2330 which are potentially related to chemotherapy and radiotherapy; underlying immune dysfunction; or shared risk factors, such as immunodeficiency, selected viral infections (eg, HIV), lifestyle factors (eg, tobacco), and genetic susceptibility. Although treatments, immunologic alterations, and risk factors may vary by lymphoma subtype, no earlier investigation has quantified differences in risk of new malignancy by lymphoma subtype, which could provide important etiologic clues to lymphoma as well as to the second malignancies. Improving our understanding of second malignancy risks is also critical for the health of the rapidly growing population of cancer survivors. We therefore evaluated second malignancy risks among survivors of the major lymphoma subtypes (ie, CLL/SLL, DLBCL, and FL) reported to Surveillance, Epidemiology, and End Results (SEER) population-based cancer registries.

PATIENTS AND METHODS

Patients

SEER registries collect data on patient demographics, primary tumor site and morphology, first course of treatment (ie, radiotherapy, chemotherapy, immunotherapy, surgery), and follow-up for occurrence of new malignancies and vital status. Since 1990, 11 SEER registries representing approximately 13% of the US population (states of Connecticut, Hawaii, New Mexico, and Utah; metropolitan areas of Atlanta, GA; Detroit, MI; Seattle/Puget Sound, WA; and Los Angeles County, San Francisco/Oakland, and San Jose/Monterey, CA; and rural Georgia)3 also have collected data on HIV/AIDS status at NHL diagnosis (including SLL, DLBCL, and FL but not CLL). These data are estimated to identify accurately approximately 90% of patients with AIDS-related NHL.3132 We assumed that all patients with CLL did not have HIV/AIDS–related disease.

This analysis included patients of all ages who survived for at least 1 year after diagnosis during 1992 to 2006 with first primary CLL/SLL, DLBCL, or FL, as reported to a SEER registry collecting HIV/AIDS data. Eligible patients were identified by using International Classification of Diseases for Oncology, third edition (ICD-O-3)33 morphology codes (CLL/SLL: 9670, 9823; DLBCL: 9678 to 9680, 9684 [B-cell immunophenotype only]; FL: 9690 to 9691, 9695 to 9698).1,34 Together, these major subtypes include two thirds of all patients with NHL and CLL. For survivors of less common lymphomas, the rarity of specific second malignancies precluded calculation of stable risk estimates. We restricted the analysis to 1992 to 2006 to include SEER registries with HIV/AIDS data and to more accurately identify lymphoma subtypes, which have higher misclassification in earlier time periods because of changes in classification.34

Second primary invasive cancers and leukemias that developed at least 1 year after initial lymphoma diagnosis were identified via SEER registry files. The SEER standard for case ascertainment is ≥ 98%. Subsequent NHLs and lymphocytic leukemias were excluded from overall second malignancy risk estimates because of the difficulty of distinguishing disease progression from independent primary cancers.

Statistical Analysis

Patients were observed from 1 year after diagnosis with first primary CLL/SLL, DLBCL, or FL until diagnosis with a second primary invasive cancer or leukemia, last follow-up, death, or end of the study (December 31, 2006), whichever occurred first. The first year of follow-up was excluded because of heightened medical screening after a patient's initial diagnosis, which may bias second malignancy ascertainment. In our cohort, 98.2% of patients were observed through 2006; 14,271 (33.1%) died, 28,105 (65.1%) were last known alive, and 769 (1.8%) were lost to follow-up. SEER actively traces patients for vital status (eg, linkage to state death certificate files and/or national databases, contact with treating physicians), regardless of emigration from a SEER area. However, SEER does not ascertain malignancies occurring in patients who moved out of registry areas, and dates of emigration are unknown. On the basis of 2000 census data, the 5-year emigration rate among adults age 40 years or older was 5.6% for the states in this analysis (ie, CA, CT, GA, HI, MI, NM, UT, and WA).35

Comparisons with the general population.

Standardized incidence ratios (SIRs) and exact 95% CIs were used to quantify second malignancy risks by comparing the observed (O) number of second malignancies with that expected (E) in the general population (SEER*Stat software, version 6.5.1; Surveillance Research Program, National Cancer Institute, Bethesda, MD). The expected number of malignancies was calculated by using data from the 11 SEER registries with HIV/AIDS data, stratifying by age (5-year groups), sex, ethnicity (white, black, other), and calendar year (1992 to 1995, 1996 to 1999, 2000 to 2003, 2004 to 2006). All analyses were stratified by HIV/AIDS status at lymphoma diagnosis. We also evaluated second malignancy risks after CLL and SLL separately, because these entities have only recently been recognized as the same disease.1 Because second malignancy risks were generally similar after CLL and SLL (Appendix Table A1, online only), we present results for CLL/SLL combined.

Comparisons among lymphoma subtypes.

For second primary malignancies with at least 10 observed occurrences after all three lymphoma subtypes, we directly assessed differences in second malignancy risks among lymphoma subtypes (PDiff) by using a likelihood ratio test derived from multivariate Poisson regression analyses, which incorporated SEER registry general population rates (Epicure software, release 2.10; HiroSoft International, Seattle, WA) and which stratified by sex, age at lymphoma diagnosis, and latency. Additional stratification by ethnicity and calendar year did not materially affect results. For those second malignancies with a significant difference in risk (PDiff < .05) by lymphoma subtype, we additionally examined SIRs by sex, age and calendar year of lymphoma diagnosis, latency, initial treatment, and second malignancy characteristics (eg, histology) to test differences in the SIRs for these variables within each lymphoma subtype by using multivariate Poisson regression models.

RESULTS

Study Population

Among the 42,213 patients without known HIV/AIDS at lymphoma diagnosis, those with CLL/SLL were older and were more likely to be men than those with DLBCL or FL (Table 1). Chemotherapy was received as a first course of therapy by at least 83% of patients with DLBCL, 55% with FL, and 29% with CLL/SLL. Initial radiotherapy was used to treat 34% of patients with DLBCL and 21% with FL, but it was rarely used for CLL/SLL (3%). Patients with HIV/AIDS–related lymphoma (n = 932) were predominantly men, younger, and diagnosed with DLBCL.

Table 1.
Selected Characteristics of 43,145 Patients Surviving at Least 1 Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006

Second Malignancy Risks Among Patients Without Known HIV/AIDS

Among patients without known HIV/AIDS at lymphoma diagnosis, overall malignancy risk was significantly higher than expected in the general population after CLL/SLL (O = 1,450; SIR = 1.19; 95% CI, 1.13 to 1.25) and DLBCL (O = 873; SIR = 1.11; 95% CI, 1.04 to 1.19) but not after FL (O = 685; SIR = 1.03; 95% CI, 0.96 to 1.11; Table 2). Poisson regression analyses, which adjusted for age, sex, and follow-up time, confirmed that the overall second malignancy risk was significantly different among the lymphoma subtypes (PDiff < .001; Table 2). However, the risk patterns differed substantially by specific second malignancy.

Table 2.
Second Primary Malignancy Risks Among Patients Surviving at Least 1 Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006

Of the nonhematologic second malignancies, risks for lung cancer and cutaneous melanoma were elevated after the more indolent lymphomas, CLL/SLL and FL, but not after the more aggressive DLBCL (lung PDiff = .001, melanoma PDiff = .004). Survivors of CLL/SLL were also more prone than the general population to develop salivary gland, colon, anal, and thyroid cancers, whereas deficits of pancreatic and breast cancers were limited to FL survivors. In contrast, observed numbers of nonhematologic second malignancies did not differ significantly from expectation after DLBCL.

Of the hematologic second malignancies, risks for Hodgkin's lymphoma were elevated after all three lymphoma subtypes, but risks varied by lymphoma subtype (PDiff = .009), with highest risks after CLL/SLL. Acute nonlymphocytic leukemia occurred excessively after DLBCL and FL but not CLL/SLL (PDiff < .001), whereas chronic myeloid leukemia risk was elevated after DLBCL.

Lung cancer was the most common second malignancy to occur in excess, with increased risks limited to survivors of CLL/SLL (SIR = 1.44) and FL (SIR = 1.28). Patients diagnosed at younger ages (< 55 years) with CLL/SLL or FL were particularly prone to lung cancer (SIR: CLL/SLL = 2.32; FL = 2.01), with a downward trend in relative risk with increasing age after CLL/SLL (Ptrend =.005) and FL (Ptrend = .01; Table 3). Initial chemotherapy appeared to heighten lung cancer risk after CLL/SLL, but risks were elevated in all initial treatment groups. Women had somewhat greater lung cancer risk than men after FL. In analyses by histologic type, lung cancer risk after both CLL/SLL and FL appeared higher for non–small-cell than small-cell lung carcinoma, but the risk differences were not significant (CLL/SLL, Phomogeneity = .07; FL, Phomogeneity = .1).

Table 3.
Risk for Second Primary Lung and Bronchus Cancer by Age, Sex, Latency, Initial Treatment, and Histology Among Patients Without Known HIV/AIDS Surviving at Least 1 Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006 ...

Risks for cutaneous melanoma followed a pattern similar to lung cancer, with excesses limited to the more indolent lymphomas (SIR: CLL/SLL = 1.92; FL = 1.60). The melanoma risk varied by age at CLL/SLL diagnosis, with greater than two-fold risks for patients diagnosed before age 70 years (Ptrend = .02; Table 4). The excess risk after CLL/SLL was pronounced for melanomas occurring on more heavily sun-exposed sites (SIR: face/head/neck = 2.24; limbs = 2.09) and for melanomas ≥ 1 mm thick (SIR: 1.0 to 3.9 mm = 2.57; ≥ 4.0 mm = 3.30). Variations in melanoma risk among FL survivors by age, sex, latency, initial treatment, and melanoma site and thickness were not significant.

Table 4.
Risk for Second Primary Melanoma by Age, Sex, Latency, Initial Treatment, Site, and Thickness Among Patients Without Known HIV/AIDS Surviving at Least 1 Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006

Although risk for Hodgkin's lymphoma was elevated after all three lymphoma types, the magnitude of the excess differed by subtype, with the largest risks observed after CLL/SLL (SIR: CLL/SLL = 15.11; DLBCL = 9.02; FL = 6.78; PDiff = .009). Most noteworthy were the greater than 20-fold risks of Hodgkin's lymphoma observed for patients diagnosed with CLL/SLL before age 70 years (Ptrend = .02; Table 5). Initial chemotherapy also appeared to heighten risk of Hodgkin's lymphoma after CLL/SLL. When we evaluated risks among CLL and SLL patients separately, Hodgkin's lymphoma risk was higher after CLL than SLL (Appendix Table A1). Hodgkin's lymphoma risk after DLBCL and FL did not differ significantly by age, sex, latency, or initial treatment.

Table 5.
Risk for Second Primary Hodgkin's Lymphoma by Age, Sex, Latency, and Initial Treatment Among Patients Without Known HIV/AIDS Surviving at Least 1Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006

Elevated risks were observed for acute nonlymphocytic leukemia after DLBCL (SIR = 4.96) and FL (SIR = 5.96) but not after CLL/SLL (SIR = 1.13; PDiff < .001). Initial chemotherapy contributed strongly to the increased risk of acute nonlymphocytic leukemia: 87% (ie, 62 of 71 patients) of the occurrences after DLBCL and FL developed in patients who received initial chemotherapy (Table 6). Acute nonlymphocytic leukemia risk also varied by age at DLBCL or FL diagnosis, with greater than 15-fold risks observed for patients diagnosed at younger ages (< 55 years) and a downward trend in risk with increasing age (Ptrend, DLBCL < .001; FL < .001). Women had greater risk of acute nonlymphocytic leukemia than men after DLBCL but not after FL. When we evaluated the risks among patients with CLL and SLL separately, acute nonlymphocytic leukemia was elevated after SLL but not after CLL (Appendix Table 1).

Table 6.
Risk for Second Primary Acute Nonlymphocytic Leukemia by Age, Sex, Latency, and Initial Treatment Among Patients Without Known HIV/AIDS Surviving at Least 1 Year After an Initial Diagnosis of CLL/SLL, DLBCL, or FL in 11 SEER Registries, 1992-2006

Second Malignancy Risks Among DLBCL Patients With HIV/AIDS

Second malignancies occurred in 49 patients with HIV/AIDS–related DLBCL (SIR = 3.81; 95% CI, 2.82 to 5.03). As expected, risks of anal cancer (O = 7; SIR = 120.50) and Kaposi's sarcoma (O = 16; SIR = 138.90) were especially striking. On the basis of smaller numbers, elevated risks were also observed for buccal cavity cancers, Hodgkin's lymphoma, and acute nonlymphocytic leukemia.

DISCUSSION

Although previous small studies have evaluated second malignancy risks after treatment for aggressive or indolent lymphomas,10,1617,19 we provide the first quantitative comparison of second malignancy risks among survivors of the major lymphoma subtypes in a large, population-based study. Our findings demonstrate substantial heterogeneity in the occurrence of second malignancy by lymphoma subtype, which suggests differences in etiology. Specifically, we observed significantly different patterns of second malignancy after CLL/SLL, DLBCL, and FL among patients without HIV/AIDS–related lymphoma. Most notable were elevated risks for lung cancer and melanoma after the more indolent lymphomas, CLL/SLL and FL, but not after the more aggressive DLBCL. Only CLL/SLL survivors had greater risk of developing other nonhematologic malignancies (ie, salivary gland, colon, anus, and thyroid). In contrast, we found no evidence that DLBCL survivors had heightened risks for any nonhematologic malignancy. We also observed elevated risks for Hodgkin's lymphoma after all three lymphoma subtypes, particularly CLL/SLL, and chemotherapy-related excesses of acute nonlymphocytic leukemia after DLBCL and FL.

Indolent NHLs are incurable, slow-growing lymphomas that cause few symptoms in early stages and feature a relapsing-remitting course.12 Treatment is often deferred until disease progression occurs, when an oral alkylating agent such as chlorambucil is the standard primary treatment.36 Patients with relapsed or advanced disease receive various combinations of chemotherapy, radiotherapy, immunotherapy, radioimmunotherapy, or high-dose chemoradiotherapy with stem-cell transplantation.3637 Patients with indolent NHL, particularly CLL, have well-characterized long-term immune dysfunction because of prediagnostic immune alterations, a relapsing-remitting disease course, and repeated exposure to immunosuppressive therapies over time.3839 In contrast, aggressive NHLs such as DLBCL are rapidly growing, and 30% to 50% of patients are cured with intensive initial chemotherapy with or without radiotherapy.12 The standard chemotherapy regimen for DLBCL includes cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), combined with rituximab (CHOP-R) in recent years.40 Patients refractory to initial therapy receive additional chemotherapy and high-dose chemoradiotherapy with stem-cell transplantation, though prognosis is generally poor.40

We observed excesses of lung cancer and melanoma after the more indolent lymphomas, CLL/SLL and FL, but not after the more aggressive DLBCL. Numerous studies of NHL and CLL have demonstrated associations for lung cancer10,13,14,17,18,22,25,2729 and melanoma,1113,15,22,29,30 but the mechanisms are unclear. Immunological alterations associated with lymphomas are likely to contribute, because lung cancer and melanoma occur in excess in immunosuppressed patients,4143 and inflammation and infections increase lung cancer risk.44 However, it is noteworthy that these tumors were not associated with DLBCL, the subtype most strongly linked with immune dysfunction.6 Because the excesses of lung cancer and melanoma were limited to more indolent lymphomas, it is plausible that long-term immune dysfunction from underlying disease or repeated treatments is responsible. However, the excess risks immediately after CLL/SLL and FL diagnosis suggest an intrinsic mechanism, possibly involving prediagnostic immune alterations or defects in cell cycle and apoptosis, which are more characteristic of indolent than aggressive lymphomas.45

Among Hodgkin's lymphoma survivors, epidemiologic studies have suggested that lung cancer risk is increased by radiotherapy and chemotherapy, alone or in combination with cigarette smoking.4647 These exposures may also contribute to excess lung cancer risk seen in some studies of NHL and CLL survivors.10,17,18,27,48 Although FL and CLL, but not DLBCL, may be weakly related to cigarette smoking,49,50 the lack of association with small-cell carcinomas of the lung or other strongly tobacco-related cancers argue against smoking as a primary explanation for our findings. Additional research is warranted to confirm that excess lung cancer risks are confined to CLL/SLL and FL survivors and to evaluate the effects of treatment and shared environmental and genetic risk factors. Studies that include longer-term survivors will be necessary to consider effectively the role of radiotherapy.

In this study and others, the association between NHL and melanoma occurred at all latency periods and was not clearly related to initial treatment, which suggests the influence of shared risk factors. The main environmental risk factor for melanoma, sun exposure, appears to be protective for NHL across the major subtypes.51 We therefore hypothesize that underlying immunologic and genetic risk factors contribute to the association between melanoma, CLL/SLL, and FL.52 Although the association between NHL and melanoma may be influenced by heightened medical surveillance, the excess risks seen for melanomas ≥ 1 mm thick but not for early lesions reduces the likelihood of this explanation.

We observed elevated Hodgkin's lymphoma risks among all NHL survivors, which is consistent with previous studies.11,13,17,22 Although immune dysfunction and shared risk factors may contribute to multiple, distinct lymphoid neoplasms,42,5354 diagnosis of Hodgkin's lymphoma after NHL may be complicated by overlapping morphologies that lead to diagnostic misclassification between recurrence and a second malignancy, under-reporting of a second lymphoma subtype, or histologic transformation.55 CLL/SLL propensity for transformation (ie, Richter's syndrome)56 may contribute to the higher risks seen after CLL than other subtypes. Additional research with serial clinical evaluation, detailed pathologic review, and evaluation of tumor clonality to identify transformation is necessary to clarify whether Hodgkin's lymphoma risks vary by NHL subtype.

The increased risk for acute nonlymphocytic leukemia after DLBCL and FL was primarily seen among patients receiving initial chemotherapy, especially in younger patients. This observation is consistent with previous studies that have implicated DNA-damaging agents, such as alkylating agents and topoisomerase II inhibitors, as well as nucleoside analogs in some studies.10,1618,21,22,26 Acute nonlymphocytic leukemia risks after DLBCL and FL have not been compared previously. Although DLBCL patients receive more aggressive initial chemotherapy, our data raise the hypothesis that FL and DLBCL survivors may eventually receive similar amounts of chemotherapy because of the high risk of FL relapse and multiple courses of chemotherapy.2 The increased risk after SLL but not CLL may be due to more frequent use of chemotherapy for SLL than CLL (44% v 25%).

Second malignancy risks were strikingly different in patients with HIV/AIDS–related lymphoma compared with patients without HIV/AIDS. The substantially elevated Kaposi's sarcoma risk after HIV/AIDS–related DLBCL is most likely due to the etiologic role of HIV in both malignancies,57 whereas the excesses of buccal cavity/pharynx and anal cancers are likely related to coinfection with HIV and human papillomavirus.58

The primary strength of our study was analysis of a large number of lymphoma survivors identified via population-based registry data, which eliminated the selection bias seen in hospital-based series. Additional strengths include the quantitative assessment of second malignancy risks by lymphoma subtype, distinction of patients with and without HIV/AIDS–related lymphoma, and the first comparison of malignancy risks after CLL and SLL. The similar patterns of second malignancy after CLL and SLL reinforces the notion that these diseases are different clinical manifestations of the same entity.1 We limited our analysis to patients diagnosed with lymphoma in 1992 or later to utilize the available HIV/AIDS data and to minimize lymphoma subtype misclassification.34 Although this restriction precluded comprehensive assessment of second malignancy risks among long-term lymphoma survivors, elevated risks were observed within the first 5 years after lymphoma diagnosis. Additional limitations included under-ascertainment of second malignancy risks as a result of patient migration outside SEER program areas and incomplete data on the initial course of chemotherapy, which may have attenuated our results.

In summary, our findings revealed substantial differences in second malignancy risks after CLL/SLL, DLBCL, and FL. Variations in immunologic alterations, treatments (eg, alkylating agent chemotherapy), genetic susceptibility, and other risk factors (eg, viral infections, tobacco use) among lymphoma subtypes are likely to contribute to the patterns of second malignancy risk and may provide etiologic clues to lymphoma as well.

Appendix

Table A1.

Second Primary Cancer Risks Among Patients Without Known HIV/AIDS Surviving at Least 1 Year After an Initial Diagnosis of CLL or SLL in11 SEER Registries, 1992-2006

Second Primary CancerDiagnosis
CLL/SLL
SLL
CLL
OSIR95% CIOSIR95% CIOSIR95% CI
All second primary cancers*1,4501.191.13 to 1.253081.171.05 to 1.311,1421.191.12 to 1.26
Buccal cavity, pharynx240.900.57 to 1.3340.700.19 to 1.80200.950.58 to 1.47
    Salivary gland92.811.28 to 5.33< 32.970.36 to 10.7372.771.11 to 5.70
Esophagus171.160.67 to 1.8530.990.20 to 2.88141.200.66 to 2.01
Stomach230.890.56 to 1.3330.540.11 to 1.57200.980.60 to 1.51
Colon, excluding rectum1391.201.01 to 1.42281.130.75 to 1.631111.221.01 to 1.47
Rectum, rectosigmoid junction431.110.80 to 1.4980.960.41 to 1.89351.150.80 to 1.59
Anus, anal canal, anorectum82.441.05 to 4.80< 32.710.33 to 9.8162.360.86 to 5.13
Liver120.860.44 to 1.4930.970.20 to 2.8590.820.38 to 1.56
Pancreas371.020.72 to 1.4160.770.28 to 1.67311.090.74 to 1.55
Larynx90.830.38 to 1.58< 30.900.11 to 3.2470.810.33 to 1.68
Lung, bronchus2741.421.26 to 1.60591.431.09 to 1.852151.421.24 to 1.62
Bones and joints000
Soft tissue, including heart71.130.45 to 2.33< 31.500.18 to 5.4251.030.33 to 2.40
Melanoma of the skin851.921.53 to 2.37202.151.32 to 3.33651.851.43 to 2.36
Female breast1221.010.84 to 1.20321.050.72 to 1.49900.990.80 to 1.22
Male breast52.630.85 to 6.13< 35.330.64 to 19.2431.960.40 to 5.74
Cervix uteri< 30.500.06 to 1.800< 30.680.08 to 2.46
Corpus uteri180.760.45 to 1.20< 30.170.00 to 0.94170.960.56 to 1.53
Ovary191.360.82 to 2.1330.870.18 to 2.54161.520.87 to 2.47
Prostate2720.970.85 to 1.09561.010.76 to 1.312160.960.83 to 1.09
Urinary bladder760.960.76 to 1.20130.820.43 to 1.39631.000.77 to 1.28
Kidney381.280.91 to 1.7671.110.44 to 2.28311.330.90 to 1.88
Brain, central nervous system110.890.44 to 1.5951.870.61 to 4.3760.620.23 to 1.35
Thyroid182.071.23 to 3.2752.380.77 to 5.55131.971.05 to 3.37
Hodgkin's lymphoma4115.1110.85 to 20.5069.923.64 to 21.603516.6011.56 to 23.09
Multiple myeloma201.130.69 to 1.7582.110.91 to 4.17120.860.45 to 1.51
Acute nonlymphocytic leukemia131.130.60 to 1.9362.450.90 to 5.3470.770.31 to 1.59
Chronic myeloid leukemia40.900.24 to 2.29< 31.060.03 to 5.9230.850.18 to 2.49
Kaposi's sarcoma43.370.92 to 8.62044.321.18 to 11.06
Other1091.391.14 to 1.68231.360.86 to 2.04861.401.12 to 1.73

NOTE. HIV/AIDS status was coded directly from the medical record at the time of initial non-Hodgkin's lymphoma (ie, SLL, diffuse large B-cell lymphoma, follicular lymphoma) diagnosis. SEER does not collect information on HIV/AIDS status for patients with CLL. We assumed that all patients with CLL did not have HIV/AIDS–related disease. Exact cell counts with fewer than three patients are suppressed to protect patient confidentiality.

Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; SEER, Surveillance, Epidemiology, and End Results; O, observed; SIR, standardized incidence ratio.

*All second primary cancers excluding non-Hodgkin's lymphoma, lymphocytic leukemia, and nonmelanoma skin cancer.
P < .05.
SIR and 95% CI were not reported when there were zero observed occurrences.

Table A2.

Second Primary Cancer Risks Among Patients Without Known HIV/AIDS Surviving at Least 1 Year After an Initial Diagnosis of NHL, Excluding CLL, in 11 SEER Registries, 1992-2006

Second Primary CancerRisk Analysis
OSIR95% CI
All second primary cancers*3,1411.101.06 to 1.14
Buccal cavity, pharynx560.880.66 to 1.14
    Salivary gland111.480.74 to 2.66
Esophagus270.830.55 to 1.21
Stomach711.170.91 to 1.47
Colon, excluding rectum2861.090.97 to 1.23
Rectum, rectosigmoid junction670.730.57 to 0.93
Anus, anal canal, anorectum121.420.73 to 2.48
Liver441.210.88 to 1.63
Pancreas760.910.72 to 1.14
Larynx321.340.91 to 1.88
Lung, bronchus5231.191.09 to 1.30
Bones and joints103.621.73 to 6.65
Soft tissue, including heart150.990.56 to 1.64
Melanoma of the skin1521.441.22 to 1.69
Female breast3300.920.82 to 1.02
Male breast41.010.28 to 2.60
Cervix uteri90.630.29 to 1.20
Corpus uteri650.930.72 to 1.19
Ovary401.000.71 to 1.36
Prostate5370.920.84 to 1.00
Urinary bladder1931.171.01 to 1.34
Kidney831.170.93 to 1.45
Brain, central nervous system361.180.82 to 1.63
Thyroid391.360.97 to 1.86
Hodgkin's lymphoma617.886.03 to 10.13
Multiple myeloma350.870.61 to 1.22
Acute nonlymphocytic leukemia1224.653.86 to 5.56
Chronic myeloid leukemia272.671.76 to 3.88
Kaposi's sarcoma41.150.31 to 2.94
Other1851.010.87 to 1.17

NOTE. HIV/AIDS status was coded directly from the medical record at the time of initial NHL diagnosis. SEER does not collect information on HIV/AIDS status for patients with CLL. We assumed that all patients with CLL did not have HIV/AIDS–related disease.

Abbreviations: NHL, non-Hodgkin's lymphoma; CLL, chronic lymphocytic leukemia; SEER, Surveillance, Epidemiology, and End Results; O, observed; SIR, standardized incidence ratio.

*All second primary cancers excluding NHL, lymphocytic leukemia, and nonmelanoma skin cancer.
P < .05.

Footnotes

Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Lindsay M. Morton, Rochelle E. Curtis, Martha S. Linet, Elizabeth C. Bluhm

Collection and assembly of data: Lynn A.G. Ries

Data analysis and interpretation: Lindsay M. Morton, Rochelle E. Curtis, Martha S. Linet, Elizabeth C. Bluhm, Margaret A. Tucker, Neil Caporaso, Lynn A.G. Ries, Joseph F. Fraumeni Jr

Manuscript writing: All authors

Final approval of manuscript: All authors

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