Second Primary Malignancies in Marginal Zone Lymphoma Survivors
Authors: Ahuja Kriti , Roy Arya Mariam 
Published: December 2024

BACKGROUND
Marginal zone lymphoma (MZL) is an indolent non Hodgkin lymphoma (NHL) occurring in the setting of chronic antigenic stimulation such as Helicobacter pylori infections or Hepatitis C and may regress with treatment of the underlying infection. However, some may require treatment of the lymphoma with systemic therapy. We aimed to study the incidence of Second Primary Malignancies (SPM), in this patient population.

METHODS
We conducted a retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) 17 registries database and identified the cases diagnosed with MZL as their primary malignancy between the years 2000 to 2021. The standardized incidence ratio (SIR = Observed/expected cases) and absolute excess risk (AER) for development of SPMs in MZL were calculated. The analysis was stratified by the receipt of chemotherapy (CT).

RESULTS
A total of 27160 MZL cases were included in the SPM analysis, of which 20003 were in the No/unknown CT group, while 7157 received CT. Regardless of receipt of CT, MZL survivors had an elevated risk for SPM compared to the general population with overall SIR for all sites 1.52 in the No/unknown CT group and 1.8 in the CT group (p&lt;0.05). The overall risk of stomach cancer was elevated in both groups, with SIR 2.13 in the no/unknown CT group and 2.56 in the CT group (p&lt;0.05). The No/unknown CT group demonstrated a significant risk (p&lt;0.05) for development of stomach cancer at all latencies with SIR 3.39 at 2-11 months, 1.93 at 1-5 years (y), 2.04 at 5-10 y and 1.98 beyond 10 y. For the CT group, the statistically significant risk of developing stomach cancer was highest at a latency of 1-5 y with SIR of 3.01. They continued to demonstrate an elevated risk at 5-10 y with SIR to 2.52 (p&lt;0.05) but did not demonstrate statistically significant risk beyond 10 y. Interestingly, these patients are at a higher risk of hepatobiliary malignancies, particularly hepatic for which overall SIR is 1.52 in No/unknown CT group and 2.01 in CT group (p&lt;0.05). MZL survivors are also at elevated risk for lung and bronchus cancers with overall SIR 1.37 in No/unknown CT group and 1.71 in CT group (p&lt;0.05), with the CT group demonstrating significant SIR (p&lt;0.05) at all latencies (1.83 beyond 10 y, 1.78 at 5-10 y, 1.41 at 1-5 y and 2.41 at 2-11 months. Interestingly, the No/unknown CT group demonstrated statistically significant reduction in risk for colorectal malignancies with overall SIR 0.83 (p&lt;0.05), and SIR 0.72 (p&lt;0.05) at 5-10 y. On the other hand, the CT group demonstrated an elevated risk for cancers of the colon, excluding the rectum with overall SIR 1.35 (p&lt;0.05), particularly affecting the cecum (SIR 1.8, p&lt;0.05) and splenic flexure (SIR 3.1, p&lt;0.05). In terms of hematological malignancies, both groups demonstrate elevated risk for lymphoid and hematopoietic diseases which declines over the years but remains statistically significant throughout - overall SIR 4.68 in No/Unknown CT group and 6.24 in CT group (p&lt;0.05). The overall SIR for SPM lymphomas is 7.17 in No/unknown CT group and 9.69 in CT group (p&lt;0.05). Both groups are at increased risk for NHL - 7.08 in No/Unknown CT group and 9.67 in CT group (p&lt;0.05), and both groups are at elevated risk for NHL at all latencies. Both groups are at increased risk for Hodgkin Lymphoma (nodal) - 9.2 in No/Unknown CT group and 10.41 in CT group (p&lt;0.05), which peaks at a latency of 10y and beyond with SIR 13.68 in No/unknown CT group and 13.02 in CT group (p&lt;0.05). Unfortunately, both groups are at elevated risk for leukemia with overall SIR 2.68 in No/unknown CT group and 3.48 in CT group (p&lt;0.05). Further, both groups are at elevated risk for acute myeloid leukemia, which is understandably higher in the CT group with overall SIR 5.24 as compared to SIR 2.07 in the No/unknown CT group (p&lt;0.05).

CONCLUSION
Patients with marginal zone lymphomas are at an elevated risk for several other SPMs. MZL patients are frequently by managed by surveillance alone; however, strict follow-up and survivorship care need to be offered to these patients given their high risk for other malignancies. Further research is needed to study these SPMs further to potentially tailor survivorship care, particularly for those with screening options such as lung and gastrointestinal malignancies.