PHILADELPHIA—A retrospective study has revealed factors that appear to influence a person’s susceptibility to Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and other malignancies.
Study investigators looked at patients diagnosed with WM or LPL over a 20-year period and found about a 50% excess of second primary cancers in this population.
The patients had a significantly increased risk of multiple hematologic and solid tumor malignancies, and a few of these malignancies had shared susceptibility factors with WM/LPL.
The investigators believe that identifying these factors may prove useful for determining genetic susceptibility to WM/LPL.
Mary L. McMaster, MD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues presented these findings at the AACR Annual Meeting 2015 (abstract 3709).
The team used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SSER) database to evaluate the risk of subsequent primary cancer in 3825 patients diagnosed with WM (n=2163) or LPL (n=1662) from 1992 to 2011. The patients’ median age was 70, most of them were male (n=2221), and most were white (n=3153).
Dr McMaster said she and her colleagues looked at both WM and LPL in this study because SEER does not include information about immunoglobulin subtype, which makes it difficult to identify all WM cases with absolute certainty.
“[D]epending on what information a pathologist has when they review a bone marrow biopsy, for example, they may or may not know whether there’s IgM present,” Dr McMaster said. “So you may have a diagnosis of LPL and not have the information required to make the diagnosis of WM. For that reason, we combined both entities for this study.”
Dr McMaster and her colleagues calculated the observed-to-expected standardized incidence ratios (SIRs) for invasive cancers. After adjusting for multiple comparisons, the team found that survivors of WM/LPL had a significantly increased risk of developing a second primary malignancy (SIR=1.49).
This increased risk was seen for males and females and persisted throughout follow-up. The risk was higher for patients younger than 65 years of age (SIR=1.95).
Hematologic malignancies
WM/LPL survivors had a significantly increased risk of several hematologic malignancies. The SIR was 4.09 for all hematologic malignancies, 4.29 for lymphomas, and 3.16 for leukemias.
Dr McMaster pointed out that several lymphoma subtypes can have lymphoplasmacytic differentiation, the most common being marginal zone lymphoma. And this could potentially result in misclassification.
“So we actually ran the study with and without marginal zone lymphoma and saw no difference in the results,” she said. “So we don’t think misclassification accounts for the majority of what we’re seeing.”
The investigators found that WM/LPL survivors had the highest risk of developing Burkitt lymphoma (SIR=13.45), followed by Hodgkin lymphoma (SIR=9.80), T-cell non-Hodgkin lymphoma (SIR=6.62), mantle cell lymphoma (SIR=5.37), diffuse large B-cell lymphoma (DLBCL, SIR=4.76), multiple myeloma (SIR=4.40), any non-Hodgkin lymphoma (SIR=4.08), and acute myeloid leukemia (AML, SIR=3.27).
“Waldenström’s is known to transform, on occasion, to DLBCL,” Dr McMaster said. “So that may well account for the excess of DLBCL that we see in this population.”
She also noted that, prior to the early 2000s, WM was typically treated with alkylating agents. And alkylating agents have been linked to an increased risk of AML.
In this population, the risk of AML peaked 5 to 10 years after WM/LPL diagnosis and was only present in patients treated prior to 2002. This suggests the AML observed in this study was likely treatment-related.
Dr McMaster and her colleagues also found that WM/LPL survivors did not have a significantly increased risk of developing acute lymphocytic leukemia (SIR=0), hairy cell leukemia (SIR=0), chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR=0.97), or follicular lymphoma (SIR=2.25).
Solid tumors
WM/LPL survivors did have a significantly increased risk of certain solid tumor malignancies. The overall SIR for solid tumors was 1.21.
The risk was significant for non-epithelial skin cancers (SIR=5.15), thyroid cancers (SIR=3.13), melanoma (SIR=1.72), and cancers of the lung and bronchus (SIR=1.44) or respiratory system (SIR=1.42).
“Melanoma has an immunological basis, as does Waldenström’s, so we think there may be some shared etiology there,” Dr McMaster said.
She also noted that a strong risk factor for thyroid cancer, particularly papillary thyroid cancer, is a history of autoimmune thyroid disease.
“Autoimmune disease of any sort is a risk factor for Waldenström’s macroglobulinemia,” she said. “So again, we think there might be a basis for shared susceptibility there.”
Dr McMaster said this research suggests that multiple primary cancers may occur in a single individual because of shared genetic susceptibility, shared environmental exposures, treatment effects, or chance. She believes future research will show that both genetic and environmental factors contribute to WM.
Investigators are currently conducting whole-exome sequencing studies and genome-wide association studies in patients with familial and spontaneous WM, with the hopes of identifying genes that contribute to WM susceptibility.
