Site-specific and latency - associated second primary malignancy in follicular lymphoma survivors : A SEER MP-SIR study (2000-2022)

Abstract Background Follicular lymphoma (FL), an indolent B-cell malignancy, has seen improved long-term survival since the introduction of rituximab. However, increased longevity may be offset by a rising incidence of second primary malignancies (SPMs). Given advancements in treatment and survival, this study aims to evaluate the incidence and risk of SPMs among FL survivors in the United States between 2000 and 2022. Methods We performed a population-based study using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database (version 8.4.5). Patients diagnosed with follicular lymphoma (ICD-O-3 histology code: 9690/3) between 2000 and 2022 were identified. A multiple primary–standardized incidence ratio (MP-SIR) session in SEER*Stat was conducted to compare observed SPMs to expected malignancies in the general population. Standardized incidence ratios (SIRs), 95% confidence intervals (CIs), and p-values were calculated. Latency was categorized as <1 year, 1–5 years, and >5 years after FL diagnosis. Site-specific risks and racial disparities were analyzed. Results A total of 6,863 FL survivors were included, with 605 developing SPMs over a mean follow-up of 6.34 years. Overall, FL survivors had a 17% increased risk of developing SPMs compared to the general population (SIR: 1.17; 95% CI: 1.08–1.27; p < 0.05). Elevated SIRs were observed among: - American Indian/Alaska Native (SIR: 2.41; p < 0.05) - Asian or Pacific Islander (SIR: 2.07; p < 0.05) - Black patients (SIR: 1.63; p < 0.05) compared to White counterparts (SIR: 1.42; p < 0.05) The mean age at FL diagnosis was 63.2 years; the mean age at SPM diagnosis was 71.1 years. The average latency was 8 years. Solid tumors with significantly elevated SIRs included: - Head and neck: Floor of mouth (SIR: 2.08; 95% CI: 1.97–2.19; p < 0.005), thyroid (SIR: 1.84; 95% CI: 1.81–1.87; p < 0.005) - Musculoskeletal: Bone and joints (SIR: 1.80; 95% CI: 1.70–1.90; p < 0.005), soft tissue including heart (SIR: 1.68; 95% CI: 1.64–1.72; p < 0.005) - Dermatological: Melanoma (SIR: 1.65; 95% CI: 1.64–1.66; p < 0.005), skin excluding basal and squamous cell (SIR: 1.64; 95% CI: 1.63–1.66; p < 0.005) - Genitourinary and respiratory: Kidney (SIR: 1.49; 95% CI: 1.47–1.51; p < 0.005), urinary bladder (SIR: 1.34; p < 0.005), lung and bronchus (SIR: 1.34; 95% CI: 1.33–1.35; p < 0.005) Hematologic malignancies with elevated risk included: - Acute myeloid leukemia (SIR: 2.52; 95% CI: 2.48–2.56; p < 0.005) - Acute lymphoblastic leukemia (SIR: 2.05; 95% CI: 1.94–2.17; p < 0.005) - Acute monocytic leukemia (SIR: 1.90; 95% CI: 1.76–2.09; p < 0.005) - Non-Hodgkin lymphoma (SIR: 1.32; 95% CI: 1.30–1.33; p < 0.005) - Hodgkin lymphoma (SIR: 1.35; 95% CI: 1.29–1.41; p < 0.005) Latency analysis revealed elevated risks for thyroid, kidney, and lung cancers within the first year post-FL diagnosis. Persistent elevated risks for melanoma, bone, soft tissue tumors, NHL, and HL were observed at both 1–5 years and beyond 5 years. Conclusion Follicular lymphoma survivors face a sustained and statistically significant risk of developing a wide spectrum of second primary malignancies. The early appearance of some SPMs and the continued risk for others support the need for tailored, long-term surveillance strategies. Racial disparities, particularly among Native American and Asian populations, highlight the urgent need for equity-driven survivorship care. This study identifies long-term and site-specific second cancer risks in follicular lymphoma survivors using a large national dataset. It reveals substantial racial disparities in SPM incidence, supporting the development of equitable, personalized survivorship screening and follow-up protocols.