Introduction: Increased risk of second primary malignancies (SPMs) has been reported in Hodgkin lymphoma as well as non-Hodgkin lymphoma (NHL) patients. NHLs are heterogeneous with different genetic, immunophenotypic, and clinical features. Some NHLs are aggressive but potentially curable, such as Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), while other NHLs are indolent but generally incurable, such as follicular lymphoma (FL) and marginal zone lymphoma (MZL). We hypothesized that the risk for developing SPMs in patients with different types of NHL would differ significantly. In this study, we compared the incidences of SPMs in patients with various major types of NHL, including BL, DLBCL, mantle cell lymphoma (MCL), FL and MZL, using population-based cancer registry data.

Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with NHL. While the most updated database includes 1973-2014 data, only the more recent 1991-2014 data were used in this study. NHL cases were identified using International Classification of Disease for Oncology, third edition (ICD-O-3) morphology codes (BL: 9687; DLBCL: 9680; MCL: 9673; FL: 9690, 9691, 9695, 9698; MZL: 9699). The SEER sequence number was used to limit the study population to those who had NHL as their only primary malignancy throughout their lives (code 00), and those who had multiple primary malignancies with NHL as their first malignancy (code 01). For the latter group, information on SPMs was obtained by using the same patient code and a defined sequence number (code 02). Further study criteria included age 18 or greater, pathology confirmation of malignancy diagnosis, and having active follow-up. Categorical data were analyzed using Chi-square test, and time-to-event data were analyzed using Kaplan-Meier estimator. Case identification and all statistical analyses were performed using SAS (v9.4).

Results: A total of 154,961 patients were included in the final analyses, 3,716 with BL, 80,734 with DLBCL, 8,323 with MCL, 44,055 with FL, and 18,133 with MZL. SPMs developed in 14,357 patients, with an overall incidence of 9.26%. The incidences of SPMs varied significantly in patients with different types of NHL, with a rate of 5.22% in BL, 7.34% in DLBCL, 9.14% in MCL, 11.66% in FL, and 12.90% in MZL (Table 1). The differences of SPM incidences between any two types of NHL were statistically significant (all P < 0.05). Male and female patients with BL had similar incidences of SPMs (5.04 % vs 5.72%, P= 0.45). Male patients with DLBCL (7.98% vs 6.58%), MCL (9.58% vs 8.16%), FL (12.69% vs 10.63%) and MZL (14.46% vs 11.62%) had higher incidences of SPMs compared to female patients (all P < 0.05). Hematological malignancies (leukemia and other lymphomas) were the most common SPMs in patients with all types of NHL. With one exception (second lung cancer in BL patients), the most common solid SPMs in NHL patients were lung cancer, prostate cancer, and breast cancer, followed closely by colorectal cancer, consistent with the pattern in general population. The next most common solid SPM was melanoma, as opposed to bladder cancer in the general population. Thyroid cancer, while less common, occurred early in patients with NHL, with the shortest median time to develop SPM.

Conclusions: Close to 10% of patients with NHL developed SPMs. The incidence of SPMs correlated with the aggressiveness and potential curability of NHL, with the lowest SPM incidence in BL, followed by DLBCL, MCL, FL and MZL. Male DLBCL, MCL, FL and MZL patients had higher incidences of SPMs compared to female patients. Hematological malignancy was the most common SPM in NHL patients. The most common solid SPMs in NHL patients were lung, prostate, breast, colorectal cancers and melanoma. Thyroid cancer as a SPM tended to develop early in NHL patients. Patients with NHL must be followed long-term for SPM, a potential complication of survival.


Nowakowski: Morphosys: Consultancy, Research Funding; pharmacyclics: Consultancy; Abbvie: Consultancy; Genetech: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Nanostring: Research Funding; celgene: Consultancy, Research Funding. Wang: Juno Therapeutic: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Karus: Research Funding; Oncternal: Research Funding; Celgene: Honoraria, Research Funding; Asana: Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.