Does Gender Matter in Non-Hodgkin Lymphoma? Differences in Epidemiology, Clinical Behavior, and Therapy

Abstract

Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies worldwide. The incidence of NHL has been rising for several decades; however, in the last 20 years, it reached a plateau. NHL incidence among males is significantly higher than in females. In addition to gender itself, gravidity has a protective role against NHL occurrence. Gender also matters in terms of NHL clinical characteristics. For example, female predominance was found in three extra-nodal sites (the breast, thyroid, and the respiratory system) occasionally involved in NHL. The diagnosis of NHL during pregnancy is associated with a unique clinical behavior. It is usually diagnosed in the second or third trimester and in advanced stage. Furthermore, the histological subtype is highly aggressive, and reproductive organ involvement is common. The reduced rate of NHL among females may be explained by direct effects of estrogens on lymphoma cell proliferation or by its effect on anti-tumor immune response. Gender has an important role in responsiveness to standard B cell NHL treatment. Among older adults, women benefited more from the addition of the anti-CD20 antibody rituximab to standard chemotherapy regimens. This phenomenon can be explained by the difference in clearance rate of rituximab that was found to be significantly lower among older females than older males. In mantle cell lymphoma, women receiving lenalidomide have higher rates of response. An understanding of the mechanisms responsible for gender-associated NHL differences will ultimately improve the clinical approach, allowing for a more accurate assessment of prognosis and patient-tailored treatment.

Epidemiology and prognostic indicators in laryngeal lymphoma: A population‐based analysis

“…Our study found a male to female ratio of 1.13:1 in the incidence of laryngeal lymphoma, consistent with prior reports that men are more affected than women . Prescott et al found a relationship between pregnancy and reduced risk of B‐cell NHL, which may in part explain the slightly lower incidence of laryngeal NHL in women . Interestingly, female sex was found to be a significant determinant of OS and DSS in our study.…”

“…Increased levels of interleukin‐6 (IL‐6) in the bloodstream have been shown to be associated with decreased survival in patients with diffuse large B‐cell lymphoma . Because estrogen has been shown to decrease production of IL‐6 and lower serum IL‐6 levels, Horesh and Horowitz postulate that higher levels of estrogen may serve a protective role by decreasing the amount of serum IL‐6 present and thereby improve survival in female patients . Estrogen has also been shown in vitro to inhibit proliferation of lymphoma cells through estrogen receptor β signaling .…”

Gender Aspects in Extranodal Marginal Zone B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue: Does Sex Matter?

“…By contrast, follicular lymphoma and marginal zone lymphoma rated nearly identical (1.0-1.2) in both sexes. In addition, association of gender with distinct clinical features has been analyzed in various smaller analyses [6], revealing that extranodal involvement of the breast, thyroid and respiratory system is more likely in female patients with DLBCL [6,7]. …”

Female reproductive factors and risk of lymphoid neoplasm: The Japan Public Health Center‐based Prospective Study

“…Worldwide, lymphoid neoplasms are generally more common in men than women for most subtypes . Although the reason for this discrepancy is not clear, one possible explanation is immune‐mediated associations of sex hormones with lymphomagenesis . In particular, estrogens have important immunomodulatory roles, including a biphasic effect on regulating immune responses, release of relevant cytokines, induction of B‐cell differentiation, and induction of proliferation or apoptosis through hormone receptors …”

“…2 Although the reason for this discrepancy is not clear, one possible explanation is immune-mediated associations of sex hormones with lymphomagenesis. [3][4][5] In particular, estrogens have important immunomodulatory roles, including a biphasic effect on regulating immune responses, release of relevant cytokines, induction of B-cell differentiation, and induction of proliferation or apoptosis through hormone receptors. [5][6][7][8] Previous studies have hypothesized that there is a link between lymphomagenesis and female reproductive factors through long-term and high exposure to female sex hormones.…”