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Mutual Risks of Cutaneous Melanoma and Specific Lymphoid Neoplasms: Second Cancer Occurrence and Survival

Mutual Risks of Cutaneous Melanoma and Specific Lymphoid Neoplasms: Second Cancer Occurrence and... Background: It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact. Methods: We identified a cohort of Caucasian adults (age 20–83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000–2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression. Results: Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR ¼ 1.96, 95% confidence interval [CI] ¼ 1.74 to 2.21), follicular lymphoma (SIR ¼ 1.32, 95% CI ¼ 1.09 to 1.58), and plasma cell neoplasms (SIR ¼ 1.33, 95% CI ¼ 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR ¼ 1.44, 95% CI ¼ 1.25 to 1.66; SIR ¼ 1.47, 95% CI ¼ 1.21 to 1.77; SIR ¼ 1.25, 95% CI ¼ 1.06 to 1.47; respectively). Risk for CM was statisti- cally significantly elevated after diffuse large B-cell lymphoma (SIR ¼ 1.22, 95% CI ¼ 1.02 to 1.45) and Hodgkin lymphoma (SIR ¼ 1.75, 95% CI ¼ 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associa- tions between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly in- creased risk of death (hazard ratio [HR] range ¼ 1.52, 95% CI ¼ 1.25 to 1.85, to 2.46, 95% CI ¼ 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range ¼ 1.75, 95% CI ¼ 1.15 to 2.65, to 6.28, 95% CI ¼ 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes. Conclusions: Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival. An association between development of cutaneous melanoma populations often undergoing careful surveillance following (CM) and lymphoid neoplasms (LNs) was first recognized over their first cancer. half a century ago (1–4). Since that time, studies have consis- Major advances in our understanding of LN have led to the tently shown that LN survivors have increased risk of develop- recognition that specific disease subtypes are heterogeneous in ing CM, and CM survivors have increased risk of developing LNs terms of etiology and clinical course, including treatment ap- (5–8). Additionally, some studies have suggested that malignan- proach, characteristic immune alterations, and prognosis. cies developing in this setting may adversely impact survival, However, it is unclear whether the association between LNs and particularly for CMs occurring after LN (9–12), despite these CM varies among the heterogeneous LN subtypes. A previous Received: November 15, 2017; Revised: January 22, 2018; Accepted: March 2, 2018 Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US. 1248 Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1249 study using Surveillance, Epidemiology, and End Results (SEER) less, localized and greater than 1.0 mm thick, regional/distant, Program cancer registry data in the United States (US) during and missing (unknown stage or unknown thickness with local- 1992–2006 reported elevated risk of CM after chronic lympho- ized disease). More than 91% of first primary CM patients re- cytic leukemia/small lymphocytic lymphoma (CLL/SLL) and fol- ceived surgery alone as initial treatment (no known licular lymphoma (FL) but not diffuse large B-cell lymphoma chemotherapy or radiation); therefore, CM treatment was not (DLBCL) (13). However, risks for other LN subtypes were not analyzed. Because sun exposure is a major risk factor for CM evaluated in that study, and to our knowledge previous studies but this information is not collected in SEER, we approximated have not evaluated the risk of most LN subtypes after CM. sun exposure based on geographic region (Table 1) and evalu- We conducted a comprehensive investigation of the associa- ated anatomic location of CM as a proxy for sun exposure (head tion between development of CM and LN subtypes using SEER and neck, trunk, limb, and other). data from 2000 to 2014, coinciding with the introduction of the World Health Organization (WHO) classification of LN (14) and inclusion of additional SEER registries. The aims of our study were 1) to quantify risk of developing second primary CM after Statistical Analysis subtype-specific first primary LNs and assess clinical impact and, conversely, 2) to quantify risk of developing subtype- We conducted a series of analyses to address the aims of this specific second primary LNs after first primary CM and assess study. First, we evaluated risk for developing incident second clinical impact. primary CM after first primary subtype-specific LN. Risk was quantified using standardized incidence ratios (SIRs) and exact, Poisson-based 95% confidence intervals (CIs), comparing the Methods number of observed CM cases after LN with that expected in the general population (SEER*Stat version 8.3.2). The expected num- Study Population ber of cases was calculated by multiplying general population CM incidence rates for Caucasians (stratified by age [five-year Eligible patients included adults who were diagnosed with first groups], sex, and calendar year [2000–2004, 2005–2009, 2010– primary LNs or CM during 2000–2013 at age 20 to 83 years and 2014]) by the person-time at risk of the LN patient cohort. survived one or more years following diagnosis, as reported to Patients were followed from one year after their first primary 17 SEER registries (Table 1)(15). Collectively, these registries rep- LN diagnosis to the earliest of: second primary malignancy diag- resent approximately one-quarter of the US population. We ex- nosis, last known follow-up, death, attained age 85 years, or end cluded non-Caucasian individuals and those younger than age of study (December 31, 2014). The first year following first pri- 20 years at first primary diagnosis due to very low rates of CM in mary LN diagnosis was excluded to avoid biases from increased these populations. We also excluded individuals with first pri- medical surveillance, whereas person-time at age 85 years or mary LNs who were known HIV-positive, which may affect CM older was excluded to avoid potential underascertainment due risk (16). to decreased medical surveillance in this oldest age group. For each LN subtype investigated, SIRs were calculated overall and stratified by key patient characteristics (Table 1). We then quan- Lymphoid Neoplasm and Cutaneous Melanoma Data tified risk of developing subtype-specific LNs after CM com- SEER captures patient demographics, vital status (including pared with the general population by estimating SIRs overall cause of death), and all incident malignancy diagnoses that oc- and by key patient characteristics. cur among residents in the registry areas (95% case ascertain- Using the observed and expected numbers of cases com- ment). For each diagnosis, SEER collects morphology and puted in SEER*Stat, we then constructed multivariable Poisson topography (defined by the International Classification of Disease regression models to evaluate whether SIRs varied across strata for Oncology, 3rd edition [ICD-O-3]) (17), stage of disease, se- of patient characteristics for each LN subtype separately quence (eg, first primary, second primary), initial course of (Epicure version 2.0) (20). In these Poisson models, the observed treatment, and other disease-specific information (eg, CM number of cases was the outcome and the log of the corre- thickness). sponding expected number of cases was included as an offset to We identified LNs using ICD-O-3 morphology codes, grouped indirectly adjust for attained age and calendar year (21). Models according to the WHO classification (14,18), and included the six were further adjusted for sex, age at first primary diagnosis, and most common LN subtypes: DLBCL, FL, CLL/SLL, marginal zone time since first primary cancer diagnosis through stratification. lymphoma (MZL), plasma cell neoplasm (PCN), and Hodgkin Two-sided P values for heterogeneity and trend tests were de- lymphoma (HL) (Table 1). For all subtypes, initial course of treat- rived from likelihood ratio tests, comparing models’ fit with and ment was defined as any treatment (yes vs no/unknown), che- without the factor of interest. Ordinal variables were treated as motherapy (any vs no/unknown), and radiotherapy (any vs no/ continuous variables in models testing for trends. In separate unknown). LN stage was categorized according to Ann Arbor analyses including all patients, we tested for overall SIR hetero- staging for DLBCL, FL, MZL, and HL (19). Because CLL stage is not geneity across LN subtypes. captured in SEER, CLL patients with no initial treatment were Finally, we assessed the clinical impact of developing second approximated as early stage, and those who received any initial primary CM or LN by comparing risk of death from any cause af- treatment as advanced stage. SLL was categorized similarly be- ter diagnosis of a second primary cancer of interest (modeled as cause the WHO classification has grouped it with CLL since a time-dependent covariate) with risk of death in the absence of 2010. PCN stage was not analyzed because it is not captured in that second primary cancer. Separate models were fit for each SEER and cannot be approximated by initial treatment. LN subtype. Hazard ratios (HRs) and 95% CIs were calculated We identified CM using ICD-O-3 morphology and topography from Cox regression models using age as the time scale and codes. Extent of disease was categorized based on a combina- adjusting for sex and year of first primary diagnosis (SAS 9.4, tion of stage and tumor thickness: localized and 1.0 mm thick or Cary, NC). Patients were followed from one year after their first ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1250 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 1. Select characteristics, by initial neoplasm, of 1-year Caucasian adult survivors of first primary lymphoid neoplasm subtypes or cutaneous melanoma, 17 SEER Program registries, 2000–2014* CLL/SLL DLBCL FL MZL PCN HL CM Characteristic (n ¼ 36 784), % (n ¼ 33 443), % (n ¼ 26 212), % (n ¼ 11 406), % (n ¼ 26 548), % (n ¼ 17 556), % (n ¼ 148 336), % Age at first primary malignancy, y 20–39 1.1 10.3 5.9 5.0 1.6 54.0 15.0 40–49 6.8 12.1 14.7 10.5 8.3 17.3 18.3 50–59 20.6 20.6 26.3 22.2 21.9 12.4 23.7 60–69 31.1 25.6 27.4 28.2 30.7 9.1 21.8 70–79 30.7 24.1 20.3 26.3 28.9 5.8 16.3 80–83 9.7 7.2 5.3 7.8 8.5 1.4 4.8 Mean age at diagnosis, y 66.2 60.8 60.6 63.2 65.2 41.6 56.5 Sex Male 60.7 54.1 49.9 45.6 56.6 53.7 55.6 Female 39.3 45.9 50.1 54.4 43.4 46.3 44.4 Year of first primary malignancy diagnosis 2000–2004 34.5 33.7 34.9 30.8 31.5 36.1 33.0 2005–2009 37.0 36.0 37.7 38.0 35.6 37.0 37.4 2010–2013 28.5 30.2 27.4 31.3 32.9 26.9 29.5 Mean follow-up time, y 4.6 4.6 5.2 4.8 3.3 6.0 5.4 Geographic region† Northern 38.3 34.1 34.9 37.0 34.9 35.7 32.2 Central 24.3 24.8 24.8 21.9 24.1 23.1 25.2 Southern 37.4 41.1 40.3 41.1 41.0 41.2 42.5 Initial course of treatment No/unknown treatment recorded 72.0 6.5 16.5 26.2 23.8 5.7 2.9 Any treatment 28.0 93.5 83.5 73.8 76.2 94.3 97.1 No/unknown CT or RT‡ 6.1 5.2 17.2 20.7 4.4 5.0 94.4 CT and RT 0.6 24.8 7.6 4.6 16.1 34.0 0.4 CT without RT 20.6 61.5 49.4 28.9 51.5 51.5 1.3 RT without CT 0.7 2.0 9.3 19.6 4.2 3.8 1.1 Stage at first primary diagnosis Lymphoid neoplasm I – 30.2 27.2 41.5 – 18.1 – II – 21.7 15.4 9.7 – 43.2 – III – 16.2 23.1 5.7 – 19.0 – IV – 26.7 27.3 28.4 – 14.7 – Unspecified – 5.2 6.9 14.6 – 5.0 – CLL/SLL§ Early stage 72.0 – – – – – – Advanced stage 28.0 – – – – – – (continued) Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1251 primary diagnosis until the earliest of: death, age 85 years, loss to follow-up, or study end date (December 31, 2014). All statistical tests were two-sided, and a P value of less than .05 was considered statistically significant. Results Study Population Analyses of first primary LN included 151 949 adults diagnosed with one of the six most common first primary LN subtypes: CLL/SLL (n ¼ 36 784), DLBCL (n ¼ 33 443), FL (n ¼ 26 212), MZL (n ¼ 11 406), PCN (n ¼ 26 548), and HL (n ¼ 17 556) (Table 1). Mean age at diagnosis ranged from 60 to 66 years for LN sub- types other than HL (41.6 years), and mean follow-up time ranged from 3.3to6.0 years. Amalepredominancewas observed for most subtypes other than FL (49.9%) and MZL (45.6%). Reported first course of treatment varied substantially by LN subtype; the majority of CLL/SLL patients had no known treatment, whereas patients with other subtypes received a range of chemotherapy (33.5% to 86.5%) and/or radiotherapy (1.3% to 37.8%). For first primary CM survivors, analyses included 148 336 adults with a mean follow-up of 5.4 years (Table 1). Mean age at diagnosis was 56.5 years with a male predominance (55.6%). CM stage was most commonly localized and 1.0 mm thick or less (62.5%). SIR Analyses Compared with the general population, the risk of developing CM was statistically significantly elevated among survivors of CLL/SLL (SIR ¼ 1.96, 95% CI ¼ 1.74 to 2.21), DLBCL (SIR ¼ 1.22, 95% CI ¼ 1.02 to 1.45), FL (SIR ¼ 1.32, 95% CI ¼ 1.09 to 1.58), PCN (SIR ¼ 1.33, 95% CI ¼ 1.07 to 1.63), and HL (SIR ¼ 1.75, 95% CI ¼ 1.33 to 2.26) and elevated, although not statistically signifi- cantly, after MZL (SIR ¼ 1.27, 95% CI ¼ 0.94 to 1.68) (Figure 1, Table 2). The magnitude of risk differed statistically signifi- cantly across subtypes of LN (P < .001). For the recip- heterogeneity rocal relationship (Figure 1, Table 3), risks of CLL/SLL (SIR ¼ 1.44, 95% CI ¼ 1.25 to 1.66), FL (SIR ¼ 1.47, 95% CI ¼ 1.21 to 1.77), and PCN (SIR ¼ 1.25, 95% CI ¼ 1.06 to 1.47) were statistically signifi- cantly higher among CM survivors compared with the general population, whereas no increase was observed for DLBCL (SIR ¼ 0.85, 95% CI ¼ 0.71 to 1.02), MZL (SIR ¼ 0.98, 95% CI ¼ 0.70 to 1.34), or HL (SIR ¼ 1.01, 95% CI ¼ 0.67 to 1.47, across LN subtypes P < .001). heterogeneity Among survivors of first primary LN, the risks for second pri- mary CM described above were largely consistent across patient subgroups based on multivariable Poisson regression analyses (Table 2). There was, however, some limited evidence of hetero- geneity. After CLL/SLL and MZL, second primary CM risk was higher in the early follow-up period (CLL/SLL P ¼ .007; heterogeneity MZL P ¼ .01). After first primary PCN, SIRs for CM de- heterogeneity creased with increasing age (P ¼ .02), were higher for trend females than males (P ¼ .008), and varied by receipt of heterogeneity initial treatment for PCN (P ¼ .05). After CLL/SLL and heterogeneity FL, second primary CM risk was highest for LN survivors resid- ing in southern regions (P ¼ .006 and .006, respectively), and trend after FL, SIRs were highest for CMs occurring on the head and neck (P ¼ .009). heterogeneity Among survivors of first primary CM, there was little hetero- geneity in risk across patient subgroups (Table 3). However, SIRs for second primary DLBCLs increased statistically significantly Table 1. (continued) CLL/SLL DLBCL FL MZL PCN HL CM Characteristic (n ¼ 36 784), % (n ¼ 33 443), % (n ¼ 26 212), % (n ¼ 11 406), % (n ¼ 26 548), % (n ¼ 17 556), % (n ¼ 148 336), % CMk Localized and 1.0 mm thick – – – – – – 62.5 Localized and >1.0 mm thick – – – – – – 18.3 Regional/distant – – – – – – 11.2 Missing stage or missing thickness for localized disease – – – – – – 8.0 *Seventeen Surveillance, Epidemiology, and End Results Program registry areas (Atlanta, Georgia; Connecticut; Detroit, Michigan; Hawaii; Iowa; New Mexico; San Francisco-Oakland, Los Angeles, and San Jose-Monterey, California; Seattle-Puget Sound, Washington; Utah; Kentucky; Louisiana; New Jersey; and areas of Rural Georgia, Greater Georgia, and Greater California). Morphology codes: CLL/SLL: 9670, 9823; DLBCL: 9678–9680, 9684 [B-cell immunopheno- type only], 9688, 9712, 9737–9738; FL: 9690–9691, 9695, 9698; MZL: 9689, 9699, 9760, 9764; PCN: 9732–9733; HL: 9650–9655, 9659, 9661–9667; melanoma: 8720–8790; and topography codes for skin (melanoma): C440–449. – ¼ not applica- ble; CLL/SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; CT ¼ chemotherapy; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lymphoma; NOS ¼ not otherwise specified; PCN ¼ plasma cell neoplasm; RT ¼ radiation; SEER ¼ Surveillance, Epidemiology, and End Results. †SEER region was categorized according to the Melanoma Risk Assessment Tool, available at https://www.cancer.gov/melanomarisktool/. Northern region includes the SEER registry areas of Connecticut; Detroit, Michigan; Iowa; Seattle-Puget Sound, Washington; and New Jersey. Central region includes SEER registry areas of San Francisco-Oakland, California; Utah; and Kentucky; as well as the following California counties: Alpine, Amador, Butte, Calaveras, Colusa, Del Norte, El Dorado, Glenn, Humboldt, Lake, Lassen, Madera, Mariposa, Mendocino, Merced, Modoc, Mono, Napa, Nevada, Placer, Plumas, Sacramento, San Joaquin, Santa Clara, Santa Cruz, Shasta, Sierra, Siskiyou, Solano, Sonoma, Stanislaus, Sutter, Tehama, Trinity, Tuolumne, Yolo, Yuba. Southern region includes the SEER registry areas of Hawaii; New Mexico; Georgia; Los Angeles, California; and Louisiana; and the following California counties: Fresno, Imperial, Inyo, Kern, Kings, Monterey, Orange, Riverside, San Benito, San Bernardino, San Diego, San Luis Obispo, Santa Barbara, Tulare, Ventura. ‡Includes “surgery alone.” §No initial treatment for CLL/SLL was used as a proxy for early stage, and any initial treatment for CLL/SLL was used as a proxy for advanced disease. kPer SEER summary stage, localized disease includes papillary dermis invaded (Clark’s level II), papillary-reticular dermal interface invaded (Clark’s level III), reticular dermis invaded (Clark’s level IV), skin/dermis, NOS, and local- ized, NOS. Regional/distant includes those with unknown stage who have “no mass found” for thickness. Thickness was missing for 6990 CM patients, and stage was missing for 4819 CM patients. ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1252 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 were not statistically significantly increased after first primary CM, and no statistically significant association was observed be- tween CM and MZL. For nearly all survivors, development of a second primary CM or LN was associated with statistically sig- nificantly higher risk of death, highlighting the clinical impact of developing second primary malignancies. Our observations are consistent with previous studies that have reported elevated risks for CM after first primary CLL/SLL in SEER (13) and other settings (22,23) and increased risks of CLL/SLL after initial CM diagnosis (8,24,25). One earlier study has also reported mutually elevated risks for CLL/SLL and CM (26). Our results are also consistent with previous SEER-based studies showing elevated risk of CM after FL (13) and PCN (27), whereas our findings of elevated risk for CM after DLBCL and PCN after CM differ from previous population-based reports, in- cluding SEER, which showed no statistically significant associa- tion (13,28). To our knowledge, this is the first study to assess risk of CM after MZL and risks of DLBCL, FL, and MZL after CM. The heterogeneity of associations between CM and specific Figure 1. Standardized incidence ratios for second primary cutaneous mela- types of LN provides insight into the etiology of these malignan- noma after first primary subtype-specific lymphoid neoplasm, and second pri- mary subtype-specific lymphoid neoplasm after first primary cutaneous cies. In particular, mutually elevated risks of CM and CLL/SLL, melanoma among one-or-more-year Caucasian adult survivors in 17 FL, and PCN may be suggestive of shared etiologic factors (29). Surveillance, Epidemiology, and End Results Program registries, 2000–2014. An immune link has long been thought to underlie mutually Standardized incidence ratios and exact, Poisson-based 95% confidence inter- elevated risks of CM and LN (30). Populations that experience vals (represented by error bars) compared the number of observed cases with prolonged broad immunosuppression, such as solid organ that expected in the general population. See Tables 2 and 3 for the population transplant recipients and individuals with HIV/AIDS, have mod- sizes and observed number of cases. CLL/SLL ¼ chronic lymphocytic leukemia/ small lymphocytic leukemia; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follic- erately increased risk for melanoma and strikingly increased ular lymphoma; MZL ¼ marginal zone lymphoma; PCN ¼ plasma cell neoplasm; risk for LN, particularly DLBCL and MZL (16,31–35). However, HL ¼ Hodgkin lymphoma; SIR ¼ standardized incidence ratio. whereas we observed mutually elevated risks for CM with CLL/ SLL, FL, and PCN, there was no evidence for increased risk of with increasing age at CM diagnosis (P ¼ .002). For FL and DLBCL and MZL after CM. Several lines of evidence point specifi- trend HL, elevated risks for were more pronounced for early-stage dis- cally to T-cell dysfunction as a plausible explanation for the ease (FL P ¼ .05; HL P ¼ .04). trend trend mutually elevated risks we observed, with the strongest data for CM after CLL/SLL. Following a diagnosis of CLL/SLL, patients typ- ically experience a relapsing/remitting disease course charac- Survival terized by progressive immunosuppression and elevated risk for infection (36–38). Investigations of specific immune defects Development of second primary CM was associated with in- in CLL/SLL describe a complex immunomodulatory effect of ma- creased risk of mortality from any cause after first primary CLL/ lignant leukemia cells that results in defects in certain T-cell SLL (HR ¼ 1.52, 95% CI ¼ 1.25 to 1.85), DLBCL (HR ¼ 1.82, 95% CI ¼ populations, leading to an overall decrease in helper activity 1.30 to 2.55), FL (HR ¼ 1.58, 95% CI ¼ 1.11 to 2.27), or HL (HR ¼ and increase in regulatory (immunosuppressive) activity 2.46, 95% CI ¼ 1.45 to 4.16) but not after MZL (HR ¼ 1.19, 95% CI ¼ (30,39,40). Consistent with this hypothesis, one study of CLL/SLL 0.57 to 2.50) or PCN (HR ¼ 1.04, 95% CI ¼ 0.73 to 1.48) (Table 4). survivors demonstrated increased risk of CM associated with re- Risks were higher for regional/distant CM occurring after CLL/ ceipt of fludarabine, which is known to deplete T-helper cells, SLL (HR ¼ 5.00, 95% CI ¼ 3.53 to 7.07), DLBCL (HR ¼ 7.87, 95% CI ¼ and history of T-cell-activating autoimmune conditions, such 4.96 to 12.51), and FL (HR ¼ 5.30, 95% CI ¼ 2.65 to 10.61) than for as Graves’ disease, psoriasis, chronic rheumatic heart disease, localized CM (Supplementary Table 1, available online). Among localized scleroderma/psoriasis, and asthma (41). Additionally, CM survivors, development of second primary LN was associ- the predominantly T-cell inflammatory infiltrate at the base of ated with increased risk of mortality from any cause, with the CMs is important prognostically (42). Less clear is whether highest risks observed after second primary PCN (HR ¼ 6.28, 95% T-cell dysfunction could explain the risk of CLL/SLL after CM or CI ¼ 5.00 to 7.88) and DLBCL (HR ¼ 5.06, 95% CI ¼ 3.84 to 6.66) the mutually increased risk of CM with PCN and FL, although and more modest risks for FL (HR ¼ 1.75, 95% CI ¼ 1.15 to 2.65) immune dysfunction also has been reported after a diagnosis of and HL (HR ¼ 3.64, 95% CI ¼ 1.89 to 6.99). PCN, FL, and CM (27,43–45). Additional research is therefore needed to understand whether specific T-cell defects may un- derlie the shared etiology of CM and CLL/SLL, FL, and PCN. Discussion Other potential shared etiologic factors to consider include In this large, population-based study among Caucasian US ultraviolet radiation (UVR) and genetic susceptibility. Although adults, we show for the first time that the association between UVR is an important risk factor for CM, epidemiologic studies CM and LN varies substantially among the six most common LN have demonstrated an inverse association for UVR with HL, subtypes. Specifically, we observed mutually increased risks for PCN, and most NHL subtypes (46–49). The similarity of the UVR second primary CM after initial diagnoses of CLL/SLL, FL, and association among LNs as well as the inverse nature of risk ar- PCN and for these same subtypes occurring as second cancers gue against UVR as an explanation for the mutually elevated after a first primary diagnosis of CM. In contrast, CM risk was el- risks we observed for CM and CLL/SLL, FL, and PCN but not evated after DLBCL and HL, but risks of second DLBCL and HL DLBCL, MZL or HL. With respect to shared inherited Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1253 Table 2. Standardized incidence ratios for second primary cutaneous melanoma by age, sex, latency, thickness, and stage among 1-year Caucasian adult survivors of first primary lymphoid neoplasms, 17 SEER Program registries, 2000–2014* Lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL (n ¼ 36 784) (n ¼ 33 443) (n ¼ 26 212) (n ¼ 11 406) (n ¼ 26 548) (n ¼ 17 556) Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Overall 287 1.96 (1.74 to 2.21) 128 1.22 (1.02 to 1.45) 119 1.32 (1.09 to 1.58) 49 1.27 (0.94 to 1.68) 91 1.33 (1.07 to 1.63) 59 1.75 (1.33 to 2.26) Age at first primary lymphoid neoplasm, y 20–39 15† 2.47 (1.38 to 4.07) 9 2.66 (1.22 to 5.05) 13† 1.25 (0.67 to 2.15) 6† 1.87 (0.69 to 4.08) 9† 2.48 (1.14 to 4.72) 19 2.15 (1.29 to 3.35) 40–49 9 1.09 (0.50 to 2.06) 8 1.26 (0.54 to 2.48) 50–59 46 1.83 (1.34 to 2.44) 24 1.18 (0.75 to 1.75) 40 1.82 (1.30 to 2.47) 9 1.16 (0.53 to 2.20) 23 1.77 (1.12 to 2.65) 18 2.65 (1.57 to 4.19) 60–69 120 2.27 (1.88 to 2.72) 48 1.41 (1.04 to 1.87) 31 0.99 (0.68 to 1.41) 19 1.47 (0.89 to 2.30) 34 1.41 (0.98 to 1.98) 14§ 1.20 (0.65 to 2.01) 70–79 94 1.71 (1.38 to 2.10) 31 0.90 (0.61 to 1.28) 35‡ 1.30 (0.91 to 1.81) 15‡ 1.02 (0.57 to 1.68) 25‡ 0.90 (0.58 to 1.33) 80–83 12 1.68 (0.87 to 2.94) 7 1.64 (0.66 to 3.38) P .07 .15 .29 .17 .02 .33 trend Sex Male 225 2.01 (1.76 to 2.29) 86 1.17 (0.94 to 1.45) 80 1.34 (1.07 to 1.67) 29 1.19 (0.80 to 1.71) 54 1.08 (0.81 to 1.41) 33 1.57 (1.08 to 2.21) Female 62 1.81 (1.39 to 2.32) 42 1.33 (0.96 to 1.80) 39 1.27 (0.90 to 1.73) 20 1.41 (0.86 to 2.18) 37 2.03 (1.43 to 2.80) 26 2.05 (1.34 to 3.01) P .45 .62 .69 .63 .008 .43 heterogeneity Latency, y <5 193 2.18 (1.88 to 2.51) 75 1.23 (0.97 to 1.54) 69 1.37 (1.07 to 1.74) 37 1.62 (1.14 to 2.23) 56 1.14 (0.86 to 1.48) 33 1.93 (1.33 to 2.72) 5 94 1.64 (1.32 to 2.00) 53 1.22 (0.91 to 1.59) 50 1.25 (0.93 to 1.64) 12 0.76 (0.39 to 1.33) 35 1.82 (1.27 to 2.53) 26 1.57 (1.02 to 2.29) P .007 .84 .52 .01 .11 .31 heterogeneity Geographic region Northern 89 1.57 (1.26 to 1.94) 37 1.03 (0.72 to 1.42) 30 0.94 (0.63 to 1.34) 16 1.11 (0.63 to 1.80) 30 1.21 (0.82 to 1.73) 18 1.43 (0.85 to 2.26) Central 71 2.05 (1.60 to 2.59) 35 1.32 (0.92 to 1.84) 27 1.24 (0.82 to 1.81) 9 1.06 (0.48 to 2.01) 24 1.48 (0.95 to 2.20) 17 2.25 (1.31 to 3.60) Southern 127 2.31 (1.93 to 2.75) 56 1.32 (1.00 to 1.72) 62 1.69 (1.30 to 2.17) 24 1.53 (0.98 to 2.28) 37 1.35 (0.95 to 1.86) 24 1.77 (1.14 to 2.64) P 0.006 .26 .006 .29 .67 .53 trend CM location Head and neck 78 1.97 (1.56 to 2.46) 36 1.37 (0.96 to 1.89) 42 1.95 (1.40 to 2.63) 14 1.47 (0. 80 to 2.47) 22 1.24 (0.78 to 1.88) 9 1.37 (0.63 to 2.61) Trunk 99 2.18 (1.77 to 2.65) 43 1.32 (0.95 to 1.77) 32 1.13 (0.78 to 1.60) 18 1.56 (0.92 to 2.46) 25 1.17 (0.76 to 1.73) 19 1.62 (0.97 to 2.53) Limb 101 1.85 (1.51 to 2.25) 44 1.07 (0.78 to 1.43) 39 1.06 (0.75 to 1.45) 15 0.94 (0.53 to 1.56) 39 1.49 (1.06 to 2.03) 27 1.92 (1.26 to 2.79) Other 9 1.38 (0.63 to 2.62) 5 1.10 (0.36 to 2.57) 6 1.55 (0.57 to 3.38) <5 1.20 (0.15 to 4.34) 5 1.66 (0.54 to 3.87) <5 3.09 (0.84 to 7.91) P .66 .34 .009 .20 .85 .81 heterogeneity CM stagek Localized and 1.0 mm thick 155 1.86 (1.58 to 2.17) 73 1.20 (0.94 to 1.51) 73 1.37 (1.08 to 1.73) 22 0.98 (0.61 to 1.48) 50 1.27 (0.94 to 1.67) 34 1.63 (1.13 to 2.28) Localized and >1.0 mm thick 69 2.23 (1.73 to 2.82) 21 0.97 (0.60 to 1.48) 26 1.42 (0.93 to 2.08) 17 2.12 (1.24 to 3.40) 19 1.34 (0.81 to 2.09) 13 2.11 (1.12 to 3.60) Regional/ distant 48 2.34 (1.73 to 3.10) 24 1.66 (1.07 to 2.47) 15 1.22 (0.68 to 2.02) 7 1.33 (0.53 to 2.74) 14 1.47 (0.81 to 2.47) 10 2.31 (1.11 to 4.25) Missing stage or missing 10 1.75 (0.84 to 3.22) <5 1.00 (0.27 to 2.57) <5 0.59 (0.07 to 2.13) <5 2.05 (0.42 to 5.99) <5 0.76 (0.09 to 2.73) 0 thickness for localized disease Missing 5 0.92 (0.30 to 2.14) 6 1.56 (0.57 to 3.40) <5 0.91 (0.19 to 2.67) 0  6 2.37 (0.87 to 5.17) <5 1.76 (0.21 to 6.37) P .10 .31 .80 .10 .55 .23 trend (continued) ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1254 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 2. (continued) Lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL (n ¼ 36 784) (n ¼ 33 443) (n ¼ 26 212) (n ¼ 11 406) (n ¼ 26 548) (n ¼ 17 556) Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Initial course of treatment Any treatment 75 1.92 (1.51 to 2.41) 117 1.20 (0.99 to 1.44) 104 1.36 (1.11 to 1.64) 38 1.35 (0.96 to 1.85) 74 1.50 (1.18 to 1.89) 58 1.84 (1.40 to 2.37) No/unknown treatment 212 1.98 (1.72 to 2.27) 11 1.54 (0.77 to 2.75) 15 1.10 (0.61 to 1.81) 11 1.05 (0.52 to 1.88) 17 0.89 (0.52 to 1.42) <5 0.48 (0.01 to 2.66) P .75 .40 .44 .46 .05 .11 heterogeneity Chemotherapy Any chemotherapy 53 1.88 (1.41 to 2.46) 105 1.18 (0.97 to 1.43) 67 1.34 (1.04 to 1.70) 20 1.62 (0.99 to 2.50) 65 1.51 (1.16 to 1.92) 53 1.92 (1.44 to 2.51) No/unknown chemotherapy 234 1.98 (1.74 to 2.26) 23 1.45 (0.92 to 2.17) 52 1.29 (0.96 to 1.69) 29 1.11 (0.74 to 1.59) 26 1.03 (0.67 to 1.51) 6 0.99 (0.36 to 2.15) P .62 .35 .89 .21 .12 .12 heterogeneity Radiation Any radiation <5 1.11 (0.13 to 4.00) 39 1.34 (0.95 to 1.83) 21 1.24 (0.77 to 1.89) 9 0.97 (0.44 to 1.83) 19 1.52 (0.91 to 2.37) 27 2.09 (1.37 to 3.03) No/unknown radiation 285 1.98 (1.75 to 2.22) 89 1.18 (0.95 to 1.45) 98 1.33 (1.08 to 1.63) 40 1.37 (0.98 to 1.86) 72 1.29 (1.01 to 1.62) 32 1.54 (1.06 to 2.18) P .38 .62 .81 .29 .58 .33 heterogeneity *SIRs and exact, Poisson-based 95% confidence intervals compared the number of observed cases with that expected in the general population (see the Methods for further details). P values to test differences in the SIRs were com- puted using a likelihood ratio test derived from Poisson regression models stratified by age at first primary lymphoid neoplasm, sex, and latency, with expected numbers of cases included as an offset. Exact numbers of cases are not reported for categories with fewer than five observed cases to maintain patient confidentiality. Tests for trend do not include missing stage or thickness. All statistical tests were two-sided. – ¼ not applicable; CI ¼ confidence interval; CLL/SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lym- phoma; O ¼ observed; PCN ¼ plasma cell neoplasm; SEER ¼ Surveillance, Epidemiology, and End Results; SIR ¼ standardized incidence ratio. †Includes age 20–49 years. ‡Includes age 70–83 years. §Includes age 60–83 years. kRegional/distant includes cases with unknown stage who have “no mass found” for thickness. Among cases with missing information on melanoma thickness, 75% had unspecified histology (morphology code: 8720). Thickness was missing for 17% of all regressing malignant melanomas (morphology code: 8723). Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1255 Table 3. Standardized incidence ratios for second primary lymphoid neoplasm incidence by age, sex, latency, and stage among 1-year Caucasian adult survivors of first primary cutaneous mela- noma, 17 SEER Program registries, 2000–2014* Second primary lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Overall 197 1.44 (1.25 to 1.66) 120 0.85 (0.71 to 1.02) 114 1.47 (1.21 to 1.77) 39 0.98 (0.70 to 1.34) 149 1.25 (1.06 to 1.47) 28 1.01 (0.67 to 1.47) Age at first primary CM, y 20–49 21 2.11 (1.31 to 3.23) 8 0.49 (0.21 to 0.97) 16 1.37 (0.78 to 2.22) 7 1.58 (0.63 to 3.25) 13 1.35 (0.72 to 2.31) 8 0.87 (0.37 to 1.71) 50–59 38 1.33 (0.94 to 1.82) 19 0.66 (0.39 to 1.02) 32 1.63 (1.12 to 2.30) 11 1.25 (0.62 to 2.24) 28 1.13 (0.75 to 1.64) 10 1.68 (0.80 to 3.08) 60–69 72 1.53 (1.20 to 1.93) 28 0.63 (0.42 to 0.91) 38 1.53 (1.08 to 2.10) 14 1.06 (0.58 to 1.78) 49 1.20 (0.89 to 1.58) 10‡ 0.80 (0.39 to 1.48) 70–79 54 1.19 (0.89 to 1.55) 59 1.30 (0.99 to 1.68) 28† 1.31 (0.87 to 1.89) 7† 0.53 (0.21 to 1.09) 59† 1.35 (1.03 to 1.74) 80–83 12 2.07 (1.07 to 3.61) 6 1.03 (0.38 to 2.24) P .14 .002 .37 .06 .85 .66 trend Sex Male 148 1.47 (1.24 to 1.73) 77 0.81 (0.64 to 1.02) 76 1.59 (1.25 to 1.99) 18 0.76 (0.45 to 1.20) 100 1.20 (0.97 to 1.45) 19 1.09 (0.65 to 1.70) Female 49 1.35 (1.00 to 1.79) 43 0.93 (0.68 to 1.26) 38 1.28 (0.91 to 1.76) 21 1.31 (0.81 to 2.00) 49 1.39 (1.03 to 1.83) 9 0.89 (0.41 to 1.69) P .55 .38 .29 .13 .39 .68 heterogeneity Latency, y <5 122 1.58 (1.32 to 1.89) 76 0.98 (0.77 to 1.22) 74 1.71 (1.34 to 2.15) 19 0.88 (0.53 to 1.37) 91 1.39 (1.12 to 1.71) 18 1.13 (0.67 to 1.79) 5 75 1.25 (0.99 to 1.57) 44 0.70 (0.51 to 0.93) 40 1.17 (0.83 to 1.59) 20 1.11 (0.68 to 1.72) 58 1.08 (0.82 to 1.40) 10 0.86 (0.41 to 1.58) P .08 .26 .03 .80 .15 .41 heterogeneity Lymphoid neoplasm stage I–  33 0.90 (0.62 to 1.26) 43 2.00 (1.45 to 2.69) 17 1.11 (0.65 to 1.78) –  9 1.74 (0.80 to 3.31) II –  17 0.66 (0.39 to 1.06) 16 1.32 (0.76 to 2.15) 6 1.57 (0.57 to 3.41) –  8 0.98 (0.42 to 1.93) III –  19 0.79 (0.47 to 1.23) 28 1.52 (1.01 to 2.19) 7§ 0.46 (0.18 to 0.95) –  8§ 0.64 (0.28 to 1.26) IV –  47 1.00 (0.74 to 1.33) 24 1.19 (0.76 to 1.77) – Unspecified –  <5 0.54 (0.15 to 1.39) <5 0.57 (0.12 to 1.65) 9 1.68 (0.77 to 3.20) –  <5 1.75 (0.36 to 5.12) P – .47 .05 .08 .04 trend CLL/SLL stagek Early stage 149 1.47 (1.24 to 1.72) –  –  –  –  – Advanced stage 48 1.36 (1.00 to 1.81) –  –  –  –  – P .58 heterogeneity *SIRs and exact, Poisson-based 95% confidence intervals compared the number of observed cases with that expected in the general population (see the Methods for further details). P values to test differences in the SIRs were com- puted using a likelihood ratio test derived from Poisson regression models stratified by age at first primary melanoma, sex, and latency, with expected numbers of cases included as an offset. Exact numbers of cases are not reported for categories with fewer than five observed cases to maintain patient confidentiality. Tests for trend do not include unspecified stage. All statistical tests were two-sided. – ¼ not applicable; CI ¼ confidence interval; CLL/ SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lymphoma; O ¼ observed; PCN ¼ plasma cell neoplasm; SEER ¼ Surveillance, Epidemiology, and End Results; SIR ¼ standardized incidence ratio. †Includes age 70–83 years. ‡Includes age 60–83 years. §Includes stages III and IV. kNo initial treatment for CLL/SLL was used as a proxy for early stage, and any initial treatment for CLL/SLL was used as a proxy for advanced disease. ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1256 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 4. Risk of death due to any cause among 1-year Caucasian adult survivors who developed a second primary malignancy of interest in comparison with the risk of death among those who did not develop a second primary malignancy of interest by lymphoid neoplasm subtype, 17 SEER Program registries, 2000–2014* First primary lymphoid neoplasm First primary cutaneous melanoma Second primary cutaneous melanoma Second primary lymphoid neoplasm Lymphoid neoplasm subtype Alive Dead HR (95% CI) Alive Dead HR (95% CI) Chronic lymphocytic leukemia/small lymphocytic leukemia No second primary of interest 26 108 10 389 Ref 127 228 20 911 Ref Second primary 187 100 1.52 (1.25 to 1.85) 139 58 2.68 (2.07 to 3.46) Diffuse large B-cell lymphoma No second primary of interest 24 358 8957 Ref 127 298 20 918 Ref Second primary 94 34 1.82 (1.30 to 2.55) 69 51 5.06 (3.84 to 6.66) Follicular lymphoma No second primary of interest 20 735 5358 Ref 127 275 20 947 Ref Second primary 89 30 1.58 (1.11 to 2.27) 92 22 1.75 (1.15 to 2.65) Marginal zone lymphoma No second primary of interest 9297 2060 Ref 127 331 20 966 Ref Second primary 42 7 1.19 (0.57 to 2.50) 36 <5† Plasma cell neoplasm No second primary of interest 13 078 13 380 Ref 127 293 20 894 Ref Second primary 60 31 1.04 (0.73 to 1.48) 74 75 6.28 (5.00 to 7.88) Hodgkin lymphoma No second primary of interest 15 262 2235 Ref 127 348 20 960 Ref Second primary 45 14 2.46 (1.45 to 4.16) 19 9 3.64 (1.89 to 6.99) *Hazard ratios were estimated from multivariable Cox regression models using age as the underlying time scale and adjusting for sex and year of first primary diagno- sis (2000–2004, 2005–2009, 2010–2013). Diagnosis of a second primary malignancy was modeled as a time-dependent variable. In order to protect patient confidentially, Surveillance, Epidemiology, and End Results does not provide exact day of diagnosis, which resulted in survival dates slightly different from the SIR analysis and the following missing cases: chronic lymphocytic leukemia/small lymphocytic leukemia (n ¼ 4), diffuse large B-cell lymphoma (n ¼ 1), follicular lymphoma (n ¼ 1), plasma cell neoplasm (n ¼ 16), Hodgkin lymphoma (n ¼ 1), and melanoma (n ¼ 2). – ¼ not applicable; CI ¼ confidence interval; HR ¼ hazard ratio; SEER ¼ Surveillance, Epidemiology, and End Results. †HRs are not presented when the number of deceased cases was less than five. susceptibility, although both common and rare genetic variants with previous literature, which suggested that more advanced have been identified separately for CM (50–57) and LN (58–62), CMs tend to develop after LNs (10,11). Nevertheless, we found shared genetic factors between LN subtypes and CM have not that a diagnosis of second primary CM was associated with 1.5- been identified. to more than twofold higher risk of death among CLL/SLL, We observed statistically significantly elevated risk for CM DLBCL, FL, and HL survivors and a fivefold or higher risk of after DLBCL and HL but not for DLBCL or HL after CM; MZL fol- death among CLL/SLL, DLBCL, and FL survivors who developed lowed a similar pattern, but risk for second primary CM was not advanced CM. Notably, development of second primary CM was statistically significant. The new finding for an increased risk of associated with the highest risk of death among survivors of CM after DLBCL may stem from changes in DLBCL treatment DLBCL and HL. Among first primary CM survivors, development over time because we only included patients diagnosed since of second primary LNs statistically significantly increased risk 2000, whereas previous studies (13) included patients treated in of death, with the highest mortality observed after DLBCL and earlier calendar periods when five-year relative survival was PCN. These results resemble LN mortality in the general popula- tion, which is higher after DLBCL and PCN as compared with the lower, prior to the introduction of rituximab. Previous studies of HL survivors have suggested that the intensive systemic ther- other LN subtypes (65). apy typically used for HL may introduce long-term immune dys- The major strength of this study is the use of large-scale function (63,64), which may increase risk for subsequent CM. population registry-based data to systematically assess specific However, no study has evaluated associations for specific LN subtypes diagnosed since 2000, leveraging both the expan- agents, and detailed chemotherapy and radiation data are not sion of SEER and the introduction of the WHO classification for available in SEER. Thus, future studies evaluating CM risk after LN, which improved classification of specific disease subtypes HL should include data on treatment and markers of immune (14). Despite this large sample size, however, we were unable to dysfunction, if possible. investigate the association between CM and other less common In addition to etiologic insights, several findings merit com- LNs to investigate long-term risks (>10 years) or include non- ment from a clinical perspective. Overall, SIRs within LN sub- Caucasian populations. Lack of detailed treatment and other types were fairly consistent among patient subgroups defined clinical data precluded investigation of specific risk factors that by age, sex, calendar year, and time since diagnosis. may partly explain the observed associations. The lack of de- Additionally, among LN survivors of a given subtype, a majority tailed clinical staging data for CM may have limited our ability to detect differences in the SIRs by stage at CM. of the second CMs were diagnosed as localized disease (1.0 mm thick), and risks of CM were generally consistent across CM In conclusion, we present a comprehensive analysis demon- stage, suggesting that LN survivors are at increased risk of both strating that the association between CM and LN differs by LN early and more advanced-stage CMs. This finding contrasts subtype among Caucasian adults and that the development of Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1257 13. Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non- second primary CM or LN substantially reduces survival. Hodgkin’s lymphoma and chronic lymphocytic leukemia: Differences by Mutually increased risks were observed for CM and three sub- lymphoma subtype. J Clin Oncol. 2010;28(33):4935–4944. types of LNs: CLL/SLL, FL, and PCN. In contrast, CM risk was ele- 14. Jaffe ES, Harris NL, Stein H, et al. Pathology and Genetics: Tumours of vated after DLBCL and HL, but there was no increase in the Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2001. 15. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975- opposite direction. Further research should seek to include 2014. Bethesda, MD: National Cancer Institute; 2007. https://seer.cancer.gov/ treatment data for first and second neoplasms and characterize csr/1975_2014/. Accessed March 23, 2018. immune function in patients with subtype-specific LNs and CM 16. Olsen CM, Knight LL, Green AC. 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Mutual Risks of Cutaneous Melanoma and Specific Lymphoid Neoplasms: Second Cancer Occurrence and Survival

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10.1093/jnci/djy052
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Abstract

Background: It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact. Methods: We identified a cohort of Caucasian adults (age 20–83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000–2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression. Results: Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR ¼ 1.96, 95% confidence interval [CI] ¼ 1.74 to 2.21), follicular lymphoma (SIR ¼ 1.32, 95% CI ¼ 1.09 to 1.58), and plasma cell neoplasms (SIR ¼ 1.33, 95% CI ¼ 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR ¼ 1.44, 95% CI ¼ 1.25 to 1.66; SIR ¼ 1.47, 95% CI ¼ 1.21 to 1.77; SIR ¼ 1.25, 95% CI ¼ 1.06 to 1.47; respectively). Risk for CM was statisti- cally significantly elevated after diffuse large B-cell lymphoma (SIR ¼ 1.22, 95% CI ¼ 1.02 to 1.45) and Hodgkin lymphoma (SIR ¼ 1.75, 95% CI ¼ 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associa- tions between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly in- creased risk of death (hazard ratio [HR] range ¼ 1.52, 95% CI ¼ 1.25 to 1.85, to 2.46, 95% CI ¼ 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range ¼ 1.75, 95% CI ¼ 1.15 to 2.65, to 6.28, 95% CI ¼ 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes. Conclusions: Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival. An association between development of cutaneous melanoma populations often undergoing careful surveillance following (CM) and lymphoid neoplasms (LNs) was first recognized over their first cancer. half a century ago (1–4). Since that time, studies have consis- Major advances in our understanding of LN have led to the tently shown that LN survivors have increased risk of develop- recognition that specific disease subtypes are heterogeneous in ing CM, and CM survivors have increased risk of developing LNs terms of etiology and clinical course, including treatment ap- (5–8). Additionally, some studies have suggested that malignan- proach, characteristic immune alterations, and prognosis. cies developing in this setting may adversely impact survival, However, it is unclear whether the association between LNs and particularly for CMs occurring after LN (9–12), despite these CM varies among the heterogeneous LN subtypes. A previous Received: November 15, 2017; Revised: January 22, 2018; Accepted: March 2, 2018 Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US. 1248 Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1249 study using Surveillance, Epidemiology, and End Results (SEER) less, localized and greater than 1.0 mm thick, regional/distant, Program cancer registry data in the United States (US) during and missing (unknown stage or unknown thickness with local- 1992–2006 reported elevated risk of CM after chronic lympho- ized disease). More than 91% of first primary CM patients re- cytic leukemia/small lymphocytic lymphoma (CLL/SLL) and fol- ceived surgery alone as initial treatment (no known licular lymphoma (FL) but not diffuse large B-cell lymphoma chemotherapy or radiation); therefore, CM treatment was not (DLBCL) (13). However, risks for other LN subtypes were not analyzed. Because sun exposure is a major risk factor for CM evaluated in that study, and to our knowledge previous studies but this information is not collected in SEER, we approximated have not evaluated the risk of most LN subtypes after CM. sun exposure based on geographic region (Table 1) and evalu- We conducted a comprehensive investigation of the associa- ated anatomic location of CM as a proxy for sun exposure (head tion between development of CM and LN subtypes using SEER and neck, trunk, limb, and other). data from 2000 to 2014, coinciding with the introduction of the World Health Organization (WHO) classification of LN (14) and inclusion of additional SEER registries. The aims of our study were 1) to quantify risk of developing second primary CM after Statistical Analysis subtype-specific first primary LNs and assess clinical impact and, conversely, 2) to quantify risk of developing subtype- We conducted a series of analyses to address the aims of this specific second primary LNs after first primary CM and assess study. First, we evaluated risk for developing incident second clinical impact. primary CM after first primary subtype-specific LN. Risk was quantified using standardized incidence ratios (SIRs) and exact, Poisson-based 95% confidence intervals (CIs), comparing the Methods number of observed CM cases after LN with that expected in the general population (SEER*Stat version 8.3.2). The expected num- Study Population ber of cases was calculated by multiplying general population CM incidence rates for Caucasians (stratified by age [five-year Eligible patients included adults who were diagnosed with first groups], sex, and calendar year [2000–2004, 2005–2009, 2010– primary LNs or CM during 2000–2013 at age 20 to 83 years and 2014]) by the person-time at risk of the LN patient cohort. survived one or more years following diagnosis, as reported to Patients were followed from one year after their first primary 17 SEER registries (Table 1)(15). Collectively, these registries rep- LN diagnosis to the earliest of: second primary malignancy diag- resent approximately one-quarter of the US population. We ex- nosis, last known follow-up, death, attained age 85 years, or end cluded non-Caucasian individuals and those younger than age of study (December 31, 2014). The first year following first pri- 20 years at first primary diagnosis due to very low rates of CM in mary LN diagnosis was excluded to avoid biases from increased these populations. We also excluded individuals with first pri- medical surveillance, whereas person-time at age 85 years or mary LNs who were known HIV-positive, which may affect CM older was excluded to avoid potential underascertainment due risk (16). to decreased medical surveillance in this oldest age group. For each LN subtype investigated, SIRs were calculated overall and stratified by key patient characteristics (Table 1). We then quan- Lymphoid Neoplasm and Cutaneous Melanoma Data tified risk of developing subtype-specific LNs after CM com- SEER captures patient demographics, vital status (including pared with the general population by estimating SIRs overall cause of death), and all incident malignancy diagnoses that oc- and by key patient characteristics. cur among residents in the registry areas (95% case ascertain- Using the observed and expected numbers of cases com- ment). For each diagnosis, SEER collects morphology and puted in SEER*Stat, we then constructed multivariable Poisson topography (defined by the International Classification of Disease regression models to evaluate whether SIRs varied across strata for Oncology, 3rd edition [ICD-O-3]) (17), stage of disease, se- of patient characteristics for each LN subtype separately quence (eg, first primary, second primary), initial course of (Epicure version 2.0) (20). In these Poisson models, the observed treatment, and other disease-specific information (eg, CM number of cases was the outcome and the log of the corre- thickness). sponding expected number of cases was included as an offset to We identified LNs using ICD-O-3 morphology codes, grouped indirectly adjust for attained age and calendar year (21). Models according to the WHO classification (14,18), and included the six were further adjusted for sex, age at first primary diagnosis, and most common LN subtypes: DLBCL, FL, CLL/SLL, marginal zone time since first primary cancer diagnosis through stratification. lymphoma (MZL), plasma cell neoplasm (PCN), and Hodgkin Two-sided P values for heterogeneity and trend tests were de- lymphoma (HL) (Table 1). For all subtypes, initial course of treat- rived from likelihood ratio tests, comparing models’ fit with and ment was defined as any treatment (yes vs no/unknown), che- without the factor of interest. Ordinal variables were treated as motherapy (any vs no/unknown), and radiotherapy (any vs no/ continuous variables in models testing for trends. In separate unknown). LN stage was categorized according to Ann Arbor analyses including all patients, we tested for overall SIR hetero- staging for DLBCL, FL, MZL, and HL (19). Because CLL stage is not geneity across LN subtypes. captured in SEER, CLL patients with no initial treatment were Finally, we assessed the clinical impact of developing second approximated as early stage, and those who received any initial primary CM or LN by comparing risk of death from any cause af- treatment as advanced stage. SLL was categorized similarly be- ter diagnosis of a second primary cancer of interest (modeled as cause the WHO classification has grouped it with CLL since a time-dependent covariate) with risk of death in the absence of 2010. PCN stage was not analyzed because it is not captured in that second primary cancer. Separate models were fit for each SEER and cannot be approximated by initial treatment. LN subtype. Hazard ratios (HRs) and 95% CIs were calculated We identified CM using ICD-O-3 morphology and topography from Cox regression models using age as the time scale and codes. Extent of disease was categorized based on a combina- adjusting for sex and year of first primary diagnosis (SAS 9.4, tion of stage and tumor thickness: localized and 1.0 mm thick or Cary, NC). Patients were followed from one year after their first ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1250 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 1. Select characteristics, by initial neoplasm, of 1-year Caucasian adult survivors of first primary lymphoid neoplasm subtypes or cutaneous melanoma, 17 SEER Program registries, 2000–2014* CLL/SLL DLBCL FL MZL PCN HL CM Characteristic (n ¼ 36 784), % (n ¼ 33 443), % (n ¼ 26 212), % (n ¼ 11 406), % (n ¼ 26 548), % (n ¼ 17 556), % (n ¼ 148 336), % Age at first primary malignancy, y 20–39 1.1 10.3 5.9 5.0 1.6 54.0 15.0 40–49 6.8 12.1 14.7 10.5 8.3 17.3 18.3 50–59 20.6 20.6 26.3 22.2 21.9 12.4 23.7 60–69 31.1 25.6 27.4 28.2 30.7 9.1 21.8 70–79 30.7 24.1 20.3 26.3 28.9 5.8 16.3 80–83 9.7 7.2 5.3 7.8 8.5 1.4 4.8 Mean age at diagnosis, y 66.2 60.8 60.6 63.2 65.2 41.6 56.5 Sex Male 60.7 54.1 49.9 45.6 56.6 53.7 55.6 Female 39.3 45.9 50.1 54.4 43.4 46.3 44.4 Year of first primary malignancy diagnosis 2000–2004 34.5 33.7 34.9 30.8 31.5 36.1 33.0 2005–2009 37.0 36.0 37.7 38.0 35.6 37.0 37.4 2010–2013 28.5 30.2 27.4 31.3 32.9 26.9 29.5 Mean follow-up time, y 4.6 4.6 5.2 4.8 3.3 6.0 5.4 Geographic region† Northern 38.3 34.1 34.9 37.0 34.9 35.7 32.2 Central 24.3 24.8 24.8 21.9 24.1 23.1 25.2 Southern 37.4 41.1 40.3 41.1 41.0 41.2 42.5 Initial course of treatment No/unknown treatment recorded 72.0 6.5 16.5 26.2 23.8 5.7 2.9 Any treatment 28.0 93.5 83.5 73.8 76.2 94.3 97.1 No/unknown CT or RT‡ 6.1 5.2 17.2 20.7 4.4 5.0 94.4 CT and RT 0.6 24.8 7.6 4.6 16.1 34.0 0.4 CT without RT 20.6 61.5 49.4 28.9 51.5 51.5 1.3 RT without CT 0.7 2.0 9.3 19.6 4.2 3.8 1.1 Stage at first primary diagnosis Lymphoid neoplasm I – 30.2 27.2 41.5 – 18.1 – II – 21.7 15.4 9.7 – 43.2 – III – 16.2 23.1 5.7 – 19.0 – IV – 26.7 27.3 28.4 – 14.7 – Unspecified – 5.2 6.9 14.6 – 5.0 – CLL/SLL§ Early stage 72.0 – – – – – – Advanced stage 28.0 – – – – – – (continued) Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1251 primary diagnosis until the earliest of: death, age 85 years, loss to follow-up, or study end date (December 31, 2014). All statistical tests were two-sided, and a P value of less than .05 was considered statistically significant. Results Study Population Analyses of first primary LN included 151 949 adults diagnosed with one of the six most common first primary LN subtypes: CLL/SLL (n ¼ 36 784), DLBCL (n ¼ 33 443), FL (n ¼ 26 212), MZL (n ¼ 11 406), PCN (n ¼ 26 548), and HL (n ¼ 17 556) (Table 1). Mean age at diagnosis ranged from 60 to 66 years for LN sub- types other than HL (41.6 years), and mean follow-up time ranged from 3.3to6.0 years. Amalepredominancewas observed for most subtypes other than FL (49.9%) and MZL (45.6%). Reported first course of treatment varied substantially by LN subtype; the majority of CLL/SLL patients had no known treatment, whereas patients with other subtypes received a range of chemotherapy (33.5% to 86.5%) and/or radiotherapy (1.3% to 37.8%). For first primary CM survivors, analyses included 148 336 adults with a mean follow-up of 5.4 years (Table 1). Mean age at diagnosis was 56.5 years with a male predominance (55.6%). CM stage was most commonly localized and 1.0 mm thick or less (62.5%). SIR Analyses Compared with the general population, the risk of developing CM was statistically significantly elevated among survivors of CLL/SLL (SIR ¼ 1.96, 95% CI ¼ 1.74 to 2.21), DLBCL (SIR ¼ 1.22, 95% CI ¼ 1.02 to 1.45), FL (SIR ¼ 1.32, 95% CI ¼ 1.09 to 1.58), PCN (SIR ¼ 1.33, 95% CI ¼ 1.07 to 1.63), and HL (SIR ¼ 1.75, 95% CI ¼ 1.33 to 2.26) and elevated, although not statistically signifi- cantly, after MZL (SIR ¼ 1.27, 95% CI ¼ 0.94 to 1.68) (Figure 1, Table 2). The magnitude of risk differed statistically signifi- cantly across subtypes of LN (P < .001). For the recip- heterogeneity rocal relationship (Figure 1, Table 3), risks of CLL/SLL (SIR ¼ 1.44, 95% CI ¼ 1.25 to 1.66), FL (SIR ¼ 1.47, 95% CI ¼ 1.21 to 1.77), and PCN (SIR ¼ 1.25, 95% CI ¼ 1.06 to 1.47) were statistically signifi- cantly higher among CM survivors compared with the general population, whereas no increase was observed for DLBCL (SIR ¼ 0.85, 95% CI ¼ 0.71 to 1.02), MZL (SIR ¼ 0.98, 95% CI ¼ 0.70 to 1.34), or HL (SIR ¼ 1.01, 95% CI ¼ 0.67 to 1.47, across LN subtypes P < .001). heterogeneity Among survivors of first primary LN, the risks for second pri- mary CM described above were largely consistent across patient subgroups based on multivariable Poisson regression analyses (Table 2). There was, however, some limited evidence of hetero- geneity. After CLL/SLL and MZL, second primary CM risk was higher in the early follow-up period (CLL/SLL P ¼ .007; heterogeneity MZL P ¼ .01). After first primary PCN, SIRs for CM de- heterogeneity creased with increasing age (P ¼ .02), were higher for trend females than males (P ¼ .008), and varied by receipt of heterogeneity initial treatment for PCN (P ¼ .05). After CLL/SLL and heterogeneity FL, second primary CM risk was highest for LN survivors resid- ing in southern regions (P ¼ .006 and .006, respectively), and trend after FL, SIRs were highest for CMs occurring on the head and neck (P ¼ .009). heterogeneity Among survivors of first primary CM, there was little hetero- geneity in risk across patient subgroups (Table 3). However, SIRs for second primary DLBCLs increased statistically significantly Table 1. (continued) CLL/SLL DLBCL FL MZL PCN HL CM Characteristic (n ¼ 36 784), % (n ¼ 33 443), % (n ¼ 26 212), % (n ¼ 11 406), % (n ¼ 26 548), % (n ¼ 17 556), % (n ¼ 148 336), % CMk Localized and 1.0 mm thick – – – – – – 62.5 Localized and >1.0 mm thick – – – – – – 18.3 Regional/distant – – – – – – 11.2 Missing stage or missing thickness for localized disease – – – – – – 8.0 *Seventeen Surveillance, Epidemiology, and End Results Program registry areas (Atlanta, Georgia; Connecticut; Detroit, Michigan; Hawaii; Iowa; New Mexico; San Francisco-Oakland, Los Angeles, and San Jose-Monterey, California; Seattle-Puget Sound, Washington; Utah; Kentucky; Louisiana; New Jersey; and areas of Rural Georgia, Greater Georgia, and Greater California). Morphology codes: CLL/SLL: 9670, 9823; DLBCL: 9678–9680, 9684 [B-cell immunopheno- type only], 9688, 9712, 9737–9738; FL: 9690–9691, 9695, 9698; MZL: 9689, 9699, 9760, 9764; PCN: 9732–9733; HL: 9650–9655, 9659, 9661–9667; melanoma: 8720–8790; and topography codes for skin (melanoma): C440–449. – ¼ not applica- ble; CLL/SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; CT ¼ chemotherapy; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lymphoma; NOS ¼ not otherwise specified; PCN ¼ plasma cell neoplasm; RT ¼ radiation; SEER ¼ Surveillance, Epidemiology, and End Results. †SEER region was categorized according to the Melanoma Risk Assessment Tool, available at https://www.cancer.gov/melanomarisktool/. Northern region includes the SEER registry areas of Connecticut; Detroit, Michigan; Iowa; Seattle-Puget Sound, Washington; and New Jersey. Central region includes SEER registry areas of San Francisco-Oakland, California; Utah; and Kentucky; as well as the following California counties: Alpine, Amador, Butte, Calaveras, Colusa, Del Norte, El Dorado, Glenn, Humboldt, Lake, Lassen, Madera, Mariposa, Mendocino, Merced, Modoc, Mono, Napa, Nevada, Placer, Plumas, Sacramento, San Joaquin, Santa Clara, Santa Cruz, Shasta, Sierra, Siskiyou, Solano, Sonoma, Stanislaus, Sutter, Tehama, Trinity, Tuolumne, Yolo, Yuba. Southern region includes the SEER registry areas of Hawaii; New Mexico; Georgia; Los Angeles, California; and Louisiana; and the following California counties: Fresno, Imperial, Inyo, Kern, Kings, Monterey, Orange, Riverside, San Benito, San Bernardino, San Diego, San Luis Obispo, Santa Barbara, Tulare, Ventura. ‡Includes “surgery alone.” §No initial treatment for CLL/SLL was used as a proxy for early stage, and any initial treatment for CLL/SLL was used as a proxy for advanced disease. kPer SEER summary stage, localized disease includes papillary dermis invaded (Clark’s level II), papillary-reticular dermal interface invaded (Clark’s level III), reticular dermis invaded (Clark’s level IV), skin/dermis, NOS, and local- ized, NOS. Regional/distant includes those with unknown stage who have “no mass found” for thickness. Thickness was missing for 6990 CM patients, and stage was missing for 4819 CM patients. ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1252 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 were not statistically significantly increased after first primary CM, and no statistically significant association was observed be- tween CM and MZL. For nearly all survivors, development of a second primary CM or LN was associated with statistically sig- nificantly higher risk of death, highlighting the clinical impact of developing second primary malignancies. Our observations are consistent with previous studies that have reported elevated risks for CM after first primary CLL/SLL in SEER (13) and other settings (22,23) and increased risks of CLL/SLL after initial CM diagnosis (8,24,25). One earlier study has also reported mutually elevated risks for CLL/SLL and CM (26). Our results are also consistent with previous SEER-based studies showing elevated risk of CM after FL (13) and PCN (27), whereas our findings of elevated risk for CM after DLBCL and PCN after CM differ from previous population-based reports, in- cluding SEER, which showed no statistically significant associa- tion (13,28). To our knowledge, this is the first study to assess risk of CM after MZL and risks of DLBCL, FL, and MZL after CM. The heterogeneity of associations between CM and specific Figure 1. Standardized incidence ratios for second primary cutaneous mela- types of LN provides insight into the etiology of these malignan- noma after first primary subtype-specific lymphoid neoplasm, and second pri- mary subtype-specific lymphoid neoplasm after first primary cutaneous cies. In particular, mutually elevated risks of CM and CLL/SLL, melanoma among one-or-more-year Caucasian adult survivors in 17 FL, and PCN may be suggestive of shared etiologic factors (29). Surveillance, Epidemiology, and End Results Program registries, 2000–2014. An immune link has long been thought to underlie mutually Standardized incidence ratios and exact, Poisson-based 95% confidence inter- elevated risks of CM and LN (30). Populations that experience vals (represented by error bars) compared the number of observed cases with prolonged broad immunosuppression, such as solid organ that expected in the general population. See Tables 2 and 3 for the population transplant recipients and individuals with HIV/AIDS, have mod- sizes and observed number of cases. CLL/SLL ¼ chronic lymphocytic leukemia/ small lymphocytic leukemia; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follic- erately increased risk for melanoma and strikingly increased ular lymphoma; MZL ¼ marginal zone lymphoma; PCN ¼ plasma cell neoplasm; risk for LN, particularly DLBCL and MZL (16,31–35). However, HL ¼ Hodgkin lymphoma; SIR ¼ standardized incidence ratio. whereas we observed mutually elevated risks for CM with CLL/ SLL, FL, and PCN, there was no evidence for increased risk of with increasing age at CM diagnosis (P ¼ .002). For FL and DLBCL and MZL after CM. Several lines of evidence point specifi- trend HL, elevated risks for were more pronounced for early-stage dis- cally to T-cell dysfunction as a plausible explanation for the ease (FL P ¼ .05; HL P ¼ .04). trend trend mutually elevated risks we observed, with the strongest data for CM after CLL/SLL. Following a diagnosis of CLL/SLL, patients typ- ically experience a relapsing/remitting disease course charac- Survival terized by progressive immunosuppression and elevated risk for infection (36–38). Investigations of specific immune defects Development of second primary CM was associated with in- in CLL/SLL describe a complex immunomodulatory effect of ma- creased risk of mortality from any cause after first primary CLL/ lignant leukemia cells that results in defects in certain T-cell SLL (HR ¼ 1.52, 95% CI ¼ 1.25 to 1.85), DLBCL (HR ¼ 1.82, 95% CI ¼ populations, leading to an overall decrease in helper activity 1.30 to 2.55), FL (HR ¼ 1.58, 95% CI ¼ 1.11 to 2.27), or HL (HR ¼ and increase in regulatory (immunosuppressive) activity 2.46, 95% CI ¼ 1.45 to 4.16) but not after MZL (HR ¼ 1.19, 95% CI ¼ (30,39,40). Consistent with this hypothesis, one study of CLL/SLL 0.57 to 2.50) or PCN (HR ¼ 1.04, 95% CI ¼ 0.73 to 1.48) (Table 4). survivors demonstrated increased risk of CM associated with re- Risks were higher for regional/distant CM occurring after CLL/ ceipt of fludarabine, which is known to deplete T-helper cells, SLL (HR ¼ 5.00, 95% CI ¼ 3.53 to 7.07), DLBCL (HR ¼ 7.87, 95% CI ¼ and history of T-cell-activating autoimmune conditions, such 4.96 to 12.51), and FL (HR ¼ 5.30, 95% CI ¼ 2.65 to 10.61) than for as Graves’ disease, psoriasis, chronic rheumatic heart disease, localized CM (Supplementary Table 1, available online). Among localized scleroderma/psoriasis, and asthma (41). Additionally, CM survivors, development of second primary LN was associ- the predominantly T-cell inflammatory infiltrate at the base of ated with increased risk of mortality from any cause, with the CMs is important prognostically (42). Less clear is whether highest risks observed after second primary PCN (HR ¼ 6.28, 95% T-cell dysfunction could explain the risk of CLL/SLL after CM or CI ¼ 5.00 to 7.88) and DLBCL (HR ¼ 5.06, 95% CI ¼ 3.84 to 6.66) the mutually increased risk of CM with PCN and FL, although and more modest risks for FL (HR ¼ 1.75, 95% CI ¼ 1.15 to 2.65) immune dysfunction also has been reported after a diagnosis of and HL (HR ¼ 3.64, 95% CI ¼ 1.89 to 6.99). PCN, FL, and CM (27,43–45). Additional research is therefore needed to understand whether specific T-cell defects may un- derlie the shared etiology of CM and CLL/SLL, FL, and PCN. Discussion Other potential shared etiologic factors to consider include In this large, population-based study among Caucasian US ultraviolet radiation (UVR) and genetic susceptibility. Although adults, we show for the first time that the association between UVR is an important risk factor for CM, epidemiologic studies CM and LN varies substantially among the six most common LN have demonstrated an inverse association for UVR with HL, subtypes. Specifically, we observed mutually increased risks for PCN, and most NHL subtypes (46–49). The similarity of the UVR second primary CM after initial diagnoses of CLL/SLL, FL, and association among LNs as well as the inverse nature of risk ar- PCN and for these same subtypes occurring as second cancers gue against UVR as an explanation for the mutually elevated after a first primary diagnosis of CM. In contrast, CM risk was el- risks we observed for CM and CLL/SLL, FL, and PCN but not evated after DLBCL and HL, but risks of second DLBCL and HL DLBCL, MZL or HL. With respect to shared inherited Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1253 Table 2. Standardized incidence ratios for second primary cutaneous melanoma by age, sex, latency, thickness, and stage among 1-year Caucasian adult survivors of first primary lymphoid neoplasms, 17 SEER Program registries, 2000–2014* Lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL (n ¼ 36 784) (n ¼ 33 443) (n ¼ 26 212) (n ¼ 11 406) (n ¼ 26 548) (n ¼ 17 556) Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Overall 287 1.96 (1.74 to 2.21) 128 1.22 (1.02 to 1.45) 119 1.32 (1.09 to 1.58) 49 1.27 (0.94 to 1.68) 91 1.33 (1.07 to 1.63) 59 1.75 (1.33 to 2.26) Age at first primary lymphoid neoplasm, y 20–39 15† 2.47 (1.38 to 4.07) 9 2.66 (1.22 to 5.05) 13† 1.25 (0.67 to 2.15) 6† 1.87 (0.69 to 4.08) 9† 2.48 (1.14 to 4.72) 19 2.15 (1.29 to 3.35) 40–49 9 1.09 (0.50 to 2.06) 8 1.26 (0.54 to 2.48) 50–59 46 1.83 (1.34 to 2.44) 24 1.18 (0.75 to 1.75) 40 1.82 (1.30 to 2.47) 9 1.16 (0.53 to 2.20) 23 1.77 (1.12 to 2.65) 18 2.65 (1.57 to 4.19) 60–69 120 2.27 (1.88 to 2.72) 48 1.41 (1.04 to 1.87) 31 0.99 (0.68 to 1.41) 19 1.47 (0.89 to 2.30) 34 1.41 (0.98 to 1.98) 14§ 1.20 (0.65 to 2.01) 70–79 94 1.71 (1.38 to 2.10) 31 0.90 (0.61 to 1.28) 35‡ 1.30 (0.91 to 1.81) 15‡ 1.02 (0.57 to 1.68) 25‡ 0.90 (0.58 to 1.33) 80–83 12 1.68 (0.87 to 2.94) 7 1.64 (0.66 to 3.38) P .07 .15 .29 .17 .02 .33 trend Sex Male 225 2.01 (1.76 to 2.29) 86 1.17 (0.94 to 1.45) 80 1.34 (1.07 to 1.67) 29 1.19 (0.80 to 1.71) 54 1.08 (0.81 to 1.41) 33 1.57 (1.08 to 2.21) Female 62 1.81 (1.39 to 2.32) 42 1.33 (0.96 to 1.80) 39 1.27 (0.90 to 1.73) 20 1.41 (0.86 to 2.18) 37 2.03 (1.43 to 2.80) 26 2.05 (1.34 to 3.01) P .45 .62 .69 .63 .008 .43 heterogeneity Latency, y <5 193 2.18 (1.88 to 2.51) 75 1.23 (0.97 to 1.54) 69 1.37 (1.07 to 1.74) 37 1.62 (1.14 to 2.23) 56 1.14 (0.86 to 1.48) 33 1.93 (1.33 to 2.72) 5 94 1.64 (1.32 to 2.00) 53 1.22 (0.91 to 1.59) 50 1.25 (0.93 to 1.64) 12 0.76 (0.39 to 1.33) 35 1.82 (1.27 to 2.53) 26 1.57 (1.02 to 2.29) P .007 .84 .52 .01 .11 .31 heterogeneity Geographic region Northern 89 1.57 (1.26 to 1.94) 37 1.03 (0.72 to 1.42) 30 0.94 (0.63 to 1.34) 16 1.11 (0.63 to 1.80) 30 1.21 (0.82 to 1.73) 18 1.43 (0.85 to 2.26) Central 71 2.05 (1.60 to 2.59) 35 1.32 (0.92 to 1.84) 27 1.24 (0.82 to 1.81) 9 1.06 (0.48 to 2.01) 24 1.48 (0.95 to 2.20) 17 2.25 (1.31 to 3.60) Southern 127 2.31 (1.93 to 2.75) 56 1.32 (1.00 to 1.72) 62 1.69 (1.30 to 2.17) 24 1.53 (0.98 to 2.28) 37 1.35 (0.95 to 1.86) 24 1.77 (1.14 to 2.64) P 0.006 .26 .006 .29 .67 .53 trend CM location Head and neck 78 1.97 (1.56 to 2.46) 36 1.37 (0.96 to 1.89) 42 1.95 (1.40 to 2.63) 14 1.47 (0. 80 to 2.47) 22 1.24 (0.78 to 1.88) 9 1.37 (0.63 to 2.61) Trunk 99 2.18 (1.77 to 2.65) 43 1.32 (0.95 to 1.77) 32 1.13 (0.78 to 1.60) 18 1.56 (0.92 to 2.46) 25 1.17 (0.76 to 1.73) 19 1.62 (0.97 to 2.53) Limb 101 1.85 (1.51 to 2.25) 44 1.07 (0.78 to 1.43) 39 1.06 (0.75 to 1.45) 15 0.94 (0.53 to 1.56) 39 1.49 (1.06 to 2.03) 27 1.92 (1.26 to 2.79) Other 9 1.38 (0.63 to 2.62) 5 1.10 (0.36 to 2.57) 6 1.55 (0.57 to 3.38) <5 1.20 (0.15 to 4.34) 5 1.66 (0.54 to 3.87) <5 3.09 (0.84 to 7.91) P .66 .34 .009 .20 .85 .81 heterogeneity CM stagek Localized and 1.0 mm thick 155 1.86 (1.58 to 2.17) 73 1.20 (0.94 to 1.51) 73 1.37 (1.08 to 1.73) 22 0.98 (0.61 to 1.48) 50 1.27 (0.94 to 1.67) 34 1.63 (1.13 to 2.28) Localized and >1.0 mm thick 69 2.23 (1.73 to 2.82) 21 0.97 (0.60 to 1.48) 26 1.42 (0.93 to 2.08) 17 2.12 (1.24 to 3.40) 19 1.34 (0.81 to 2.09) 13 2.11 (1.12 to 3.60) Regional/ distant 48 2.34 (1.73 to 3.10) 24 1.66 (1.07 to 2.47) 15 1.22 (0.68 to 2.02) 7 1.33 (0.53 to 2.74) 14 1.47 (0.81 to 2.47) 10 2.31 (1.11 to 4.25) Missing stage or missing 10 1.75 (0.84 to 3.22) <5 1.00 (0.27 to 2.57) <5 0.59 (0.07 to 2.13) <5 2.05 (0.42 to 5.99) <5 0.76 (0.09 to 2.73) 0 thickness for localized disease Missing 5 0.92 (0.30 to 2.14) 6 1.56 (0.57 to 3.40) <5 0.91 (0.19 to 2.67) 0  6 2.37 (0.87 to 5.17) <5 1.76 (0.21 to 6.37) P .10 .31 .80 .10 .55 .23 trend (continued) ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1254 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 2. (continued) Lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL (n ¼ 36 784) (n ¼ 33 443) (n ¼ 26 212) (n ¼ 11 406) (n ¼ 26 548) (n ¼ 17 556) Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Initial course of treatment Any treatment 75 1.92 (1.51 to 2.41) 117 1.20 (0.99 to 1.44) 104 1.36 (1.11 to 1.64) 38 1.35 (0.96 to 1.85) 74 1.50 (1.18 to 1.89) 58 1.84 (1.40 to 2.37) No/unknown treatment 212 1.98 (1.72 to 2.27) 11 1.54 (0.77 to 2.75) 15 1.10 (0.61 to 1.81) 11 1.05 (0.52 to 1.88) 17 0.89 (0.52 to 1.42) <5 0.48 (0.01 to 2.66) P .75 .40 .44 .46 .05 .11 heterogeneity Chemotherapy Any chemotherapy 53 1.88 (1.41 to 2.46) 105 1.18 (0.97 to 1.43) 67 1.34 (1.04 to 1.70) 20 1.62 (0.99 to 2.50) 65 1.51 (1.16 to 1.92) 53 1.92 (1.44 to 2.51) No/unknown chemotherapy 234 1.98 (1.74 to 2.26) 23 1.45 (0.92 to 2.17) 52 1.29 (0.96 to 1.69) 29 1.11 (0.74 to 1.59) 26 1.03 (0.67 to 1.51) 6 0.99 (0.36 to 2.15) P .62 .35 .89 .21 .12 .12 heterogeneity Radiation Any radiation <5 1.11 (0.13 to 4.00) 39 1.34 (0.95 to 1.83) 21 1.24 (0.77 to 1.89) 9 0.97 (0.44 to 1.83) 19 1.52 (0.91 to 2.37) 27 2.09 (1.37 to 3.03) No/unknown radiation 285 1.98 (1.75 to 2.22) 89 1.18 (0.95 to 1.45) 98 1.33 (1.08 to 1.63) 40 1.37 (0.98 to 1.86) 72 1.29 (1.01 to 1.62) 32 1.54 (1.06 to 2.18) P .38 .62 .81 .29 .58 .33 heterogeneity *SIRs and exact, Poisson-based 95% confidence intervals compared the number of observed cases with that expected in the general population (see the Methods for further details). P values to test differences in the SIRs were com- puted using a likelihood ratio test derived from Poisson regression models stratified by age at first primary lymphoid neoplasm, sex, and latency, with expected numbers of cases included as an offset. Exact numbers of cases are not reported for categories with fewer than five observed cases to maintain patient confidentiality. Tests for trend do not include missing stage or thickness. All statistical tests were two-sided. – ¼ not applicable; CI ¼ confidence interval; CLL/SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lym- phoma; O ¼ observed; PCN ¼ plasma cell neoplasm; SEER ¼ Surveillance, Epidemiology, and End Results; SIR ¼ standardized incidence ratio. †Includes age 20–49 years. ‡Includes age 70–83 years. §Includes age 60–83 years. kRegional/distant includes cases with unknown stage who have “no mass found” for thickness. Among cases with missing information on melanoma thickness, 75% had unspecified histology (morphology code: 8720). Thickness was missing for 17% of all regressing malignant melanomas (morphology code: 8723). Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1255 Table 3. Standardized incidence ratios for second primary lymphoid neoplasm incidence by age, sex, latency, and stage among 1-year Caucasian adult survivors of first primary cutaneous mela- noma, 17 SEER Program registries, 2000–2014* Second primary lymphoid neoplasms CLL/SLL DLBCL FL MZL PCN HL Characteristic O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) O SIR (95% CI) Overall 197 1.44 (1.25 to 1.66) 120 0.85 (0.71 to 1.02) 114 1.47 (1.21 to 1.77) 39 0.98 (0.70 to 1.34) 149 1.25 (1.06 to 1.47) 28 1.01 (0.67 to 1.47) Age at first primary CM, y 20–49 21 2.11 (1.31 to 3.23) 8 0.49 (0.21 to 0.97) 16 1.37 (0.78 to 2.22) 7 1.58 (0.63 to 3.25) 13 1.35 (0.72 to 2.31) 8 0.87 (0.37 to 1.71) 50–59 38 1.33 (0.94 to 1.82) 19 0.66 (0.39 to 1.02) 32 1.63 (1.12 to 2.30) 11 1.25 (0.62 to 2.24) 28 1.13 (0.75 to 1.64) 10 1.68 (0.80 to 3.08) 60–69 72 1.53 (1.20 to 1.93) 28 0.63 (0.42 to 0.91) 38 1.53 (1.08 to 2.10) 14 1.06 (0.58 to 1.78) 49 1.20 (0.89 to 1.58) 10‡ 0.80 (0.39 to 1.48) 70–79 54 1.19 (0.89 to 1.55) 59 1.30 (0.99 to 1.68) 28† 1.31 (0.87 to 1.89) 7† 0.53 (0.21 to 1.09) 59† 1.35 (1.03 to 1.74) 80–83 12 2.07 (1.07 to 3.61) 6 1.03 (0.38 to 2.24) P .14 .002 .37 .06 .85 .66 trend Sex Male 148 1.47 (1.24 to 1.73) 77 0.81 (0.64 to 1.02) 76 1.59 (1.25 to 1.99) 18 0.76 (0.45 to 1.20) 100 1.20 (0.97 to 1.45) 19 1.09 (0.65 to 1.70) Female 49 1.35 (1.00 to 1.79) 43 0.93 (0.68 to 1.26) 38 1.28 (0.91 to 1.76) 21 1.31 (0.81 to 2.00) 49 1.39 (1.03 to 1.83) 9 0.89 (0.41 to 1.69) P .55 .38 .29 .13 .39 .68 heterogeneity Latency, y <5 122 1.58 (1.32 to 1.89) 76 0.98 (0.77 to 1.22) 74 1.71 (1.34 to 2.15) 19 0.88 (0.53 to 1.37) 91 1.39 (1.12 to 1.71) 18 1.13 (0.67 to 1.79) 5 75 1.25 (0.99 to 1.57) 44 0.70 (0.51 to 0.93) 40 1.17 (0.83 to 1.59) 20 1.11 (0.68 to 1.72) 58 1.08 (0.82 to 1.40) 10 0.86 (0.41 to 1.58) P .08 .26 .03 .80 .15 .41 heterogeneity Lymphoid neoplasm stage I–  33 0.90 (0.62 to 1.26) 43 2.00 (1.45 to 2.69) 17 1.11 (0.65 to 1.78) –  9 1.74 (0.80 to 3.31) II –  17 0.66 (0.39 to 1.06) 16 1.32 (0.76 to 2.15) 6 1.57 (0.57 to 3.41) –  8 0.98 (0.42 to 1.93) III –  19 0.79 (0.47 to 1.23) 28 1.52 (1.01 to 2.19) 7§ 0.46 (0.18 to 0.95) –  8§ 0.64 (0.28 to 1.26) IV –  47 1.00 (0.74 to 1.33) 24 1.19 (0.76 to 1.77) – Unspecified –  <5 0.54 (0.15 to 1.39) <5 0.57 (0.12 to 1.65) 9 1.68 (0.77 to 3.20) –  <5 1.75 (0.36 to 5.12) P – .47 .05 .08 .04 trend CLL/SLL stagek Early stage 149 1.47 (1.24 to 1.72) –  –  –  –  – Advanced stage 48 1.36 (1.00 to 1.81) –  –  –  –  – P .58 heterogeneity *SIRs and exact, Poisson-based 95% confidence intervals compared the number of observed cases with that expected in the general population (see the Methods for further details). P values to test differences in the SIRs were com- puted using a likelihood ratio test derived from Poisson regression models stratified by age at first primary melanoma, sex, and latency, with expected numbers of cases included as an offset. Exact numbers of cases are not reported for categories with fewer than five observed cases to maintain patient confidentiality. Tests for trend do not include unspecified stage. All statistical tests were two-sided. – ¼ not applicable; CI ¼ confidence interval; CLL/ SLL ¼ chronic lymphocytic leukemia/small lymphocytic leukemia; CM ¼ cutaneous melanoma; DLBCL ¼ diffuse large B-cell lymphoma; FL ¼ follicular lymphoma; HL ¼ Hodgkin lymphoma; MZL ¼ marginal zone lymphoma; O ¼ observed; PCN ¼ plasma cell neoplasm; SEER ¼ Surveillance, Epidemiology, and End Results; SIR ¼ standardized incidence ratio. †Includes age 70–83 years. ‡Includes age 60–83 years. §Includes stages III and IV. kNo initial treatment for CLL/SLL was used as a proxy for early stage, and any initial treatment for CLL/SLL was used as a proxy for advanced disease. ARTICLE Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 ARTICLE 1256 | JNCI J Natl Cancer Inst, 2018, Vol. 110, No. 11 Table 4. Risk of death due to any cause among 1-year Caucasian adult survivors who developed a second primary malignancy of interest in comparison with the risk of death among those who did not develop a second primary malignancy of interest by lymphoid neoplasm subtype, 17 SEER Program registries, 2000–2014* First primary lymphoid neoplasm First primary cutaneous melanoma Second primary cutaneous melanoma Second primary lymphoid neoplasm Lymphoid neoplasm subtype Alive Dead HR (95% CI) Alive Dead HR (95% CI) Chronic lymphocytic leukemia/small lymphocytic leukemia No second primary of interest 26 108 10 389 Ref 127 228 20 911 Ref Second primary 187 100 1.52 (1.25 to 1.85) 139 58 2.68 (2.07 to 3.46) Diffuse large B-cell lymphoma No second primary of interest 24 358 8957 Ref 127 298 20 918 Ref Second primary 94 34 1.82 (1.30 to 2.55) 69 51 5.06 (3.84 to 6.66) Follicular lymphoma No second primary of interest 20 735 5358 Ref 127 275 20 947 Ref Second primary 89 30 1.58 (1.11 to 2.27) 92 22 1.75 (1.15 to 2.65) Marginal zone lymphoma No second primary of interest 9297 2060 Ref 127 331 20 966 Ref Second primary 42 7 1.19 (0.57 to 2.50) 36 <5† Plasma cell neoplasm No second primary of interest 13 078 13 380 Ref 127 293 20 894 Ref Second primary 60 31 1.04 (0.73 to 1.48) 74 75 6.28 (5.00 to 7.88) Hodgkin lymphoma No second primary of interest 15 262 2235 Ref 127 348 20 960 Ref Second primary 45 14 2.46 (1.45 to 4.16) 19 9 3.64 (1.89 to 6.99) *Hazard ratios were estimated from multivariable Cox regression models using age as the underlying time scale and adjusting for sex and year of first primary diagno- sis (2000–2004, 2005–2009, 2010–2013). Diagnosis of a second primary malignancy was modeled as a time-dependent variable. In order to protect patient confidentially, Surveillance, Epidemiology, and End Results does not provide exact day of diagnosis, which resulted in survival dates slightly different from the SIR analysis and the following missing cases: chronic lymphocytic leukemia/small lymphocytic leukemia (n ¼ 4), diffuse large B-cell lymphoma (n ¼ 1), follicular lymphoma (n ¼ 1), plasma cell neoplasm (n ¼ 16), Hodgkin lymphoma (n ¼ 1), and melanoma (n ¼ 2). – ¼ not applicable; CI ¼ confidence interval; HR ¼ hazard ratio; SEER ¼ Surveillance, Epidemiology, and End Results. †HRs are not presented when the number of deceased cases was less than five. susceptibility, although both common and rare genetic variants with previous literature, which suggested that more advanced have been identified separately for CM (50–57) and LN (58–62), CMs tend to develop after LNs (10,11). Nevertheless, we found shared genetic factors between LN subtypes and CM have not that a diagnosis of second primary CM was associated with 1.5- been identified. to more than twofold higher risk of death among CLL/SLL, We observed statistically significantly elevated risk for CM DLBCL, FL, and HL survivors and a fivefold or higher risk of after DLBCL and HL but not for DLBCL or HL after CM; MZL fol- death among CLL/SLL, DLBCL, and FL survivors who developed lowed a similar pattern, but risk for second primary CM was not advanced CM. Notably, development of second primary CM was statistically significant. The new finding for an increased risk of associated with the highest risk of death among survivors of CM after DLBCL may stem from changes in DLBCL treatment DLBCL and HL. Among first primary CM survivors, development over time because we only included patients diagnosed since of second primary LNs statistically significantly increased risk 2000, whereas previous studies (13) included patients treated in of death, with the highest mortality observed after DLBCL and earlier calendar periods when five-year relative survival was PCN. These results resemble LN mortality in the general popula- tion, which is higher after DLBCL and PCN as compared with the lower, prior to the introduction of rituximab. Previous studies of HL survivors have suggested that the intensive systemic ther- other LN subtypes (65). apy typically used for HL may introduce long-term immune dys- The major strength of this study is the use of large-scale function (63,64), which may increase risk for subsequent CM. population registry-based data to systematically assess specific However, no study has evaluated associations for specific LN subtypes diagnosed since 2000, leveraging both the expan- agents, and detailed chemotherapy and radiation data are not sion of SEER and the introduction of the WHO classification for available in SEER. Thus, future studies evaluating CM risk after LN, which improved classification of specific disease subtypes HL should include data on treatment and markers of immune (14). Despite this large sample size, however, we were unable to dysfunction, if possible. investigate the association between CM and other less common In addition to etiologic insights, several findings merit com- LNs to investigate long-term risks (>10 years) or include non- ment from a clinical perspective. Overall, SIRs within LN sub- Caucasian populations. Lack of detailed treatment and other types were fairly consistent among patient subgroups defined clinical data precluded investigation of specific risk factors that by age, sex, calendar year, and time since diagnosis. may partly explain the observed associations. The lack of de- Additionally, among LN survivors of a given subtype, a majority tailed clinical staging data for CM may have limited our ability to detect differences in the SIRs by stage at CM. of the second CMs were diagnosed as localized disease (1.0 mm thick), and risks of CM were generally consistent across CM In conclusion, we present a comprehensive analysis demon- stage, suggesting that LN survivors are at increased risk of both strating that the association between CM and LN differs by LN early and more advanced-stage CMs. This finding contrasts subtype among Caucasian adults and that the development of Downloaded from https://academic.oup.com/jnci/article/110/11/1248/4963737 by DeepDyve user on 18 July 2022 M. M. Herr et al. | 1257 13. Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non- second primary CM or LN substantially reduces survival. 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Journal

"JNCI: Journal of the National Cancer Institute" – Oxford University Press

Published: Nov 1, 2018

Keywords: adult; lesch-nyhan syndrome; chronic b-cell leukemias; diffuse large b-cell lymphoma; small cell lymphoma; survivors; european continental ancestry group; systemic inflammatory response syndrome; cancer; heterogeneity; lymphoid neoplasm, malignant; malignant melanoma, cutaneous; second primary cancers; hodgkin's disease; follicular lymphoma; multiple myeloma; marginal zone b-cell lymphoma; causality; mortality; cox proportional hazards models

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