Certain Non-Hodgkin Lymphoma Subtypes Carry Higher Risk of Infection-Related Solid Tumor Cancers

Various subtypes of non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), carry a risk for second infection-related solid cancers, such as cancers of the oropharynx/tonsil, stomach, anus, liver, and cervix, according to a study published in Blood Advances.

“No clear recommendations exist for long-term second cancer surveillance among NHL survivors with certain infections,” study author Lindsay M. Morton, PhD, of the National Institutes of Health’s National Cancer Institute, explained. “Our findings emphasize the importance of screening for infections, since recent data suggest that an unexpected number of patients with newly diagnosed cancer are unaware that they may have certain infections, such as hepatitis B or C virus.”

However, the overall risk for second cancers was small except in patients with specific NHL subtypes and infection types, suggesting that there may not be a need for additional cancer screening in all patients with these NHL subtypes.

To evaluate which patients with NHL are at the highest risk of developing an infection-related second cancer, the researchers reviewed 17 Surveillance, Epidemiology, and End Results (SEER) Program registries to identify 127,044 adults who received their first primary NHL diagnosis between 2000 and 2014. Only patients who had survived at least one year following diagnosis were included.

Participants had the following diagnoses:

  • DLBCL (n=41,416)
  • follicular lymphoma (FL; n=29,508)
  • chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=42,119)
  • MZL (n=14,001)

Next, the study authors identified second primary infection-related solid tumors among these patients, the risk for which varied according to NHL subtype and by infection type. The risks for any second cancer were highest for patients with DLBCL and MZL, and the standardized incidence ratio (SIR), compared with the general population, was highest for liver, stomach, and anal cancers (TABLE).

Conversely, there was no increased risk for these cancer types among survivors of FL or CLL/SLL.

Furthermore, risks varied according to primary site of involvement in patients with DLBCL or MZL. For example, SIRs were higher for patients with gastric MZL versus nongastric extranodal MZL (SIR=1.67; 95% CI 0.80-3.06; p<0.01) or survivors of nodal MZL (SIR=1.48; 95% CI 0.68-2.81; p value not reported). Stomach cancer risk also was elevated in those with gastric DLBCL (SIR=2.67; 95% CI 1.07-5.50), yet this higher risk was not observed following non-gastric extranodal DLBCL (SIR=1.32; 95% CI 0.77- 2.11; p=0.12).

The incidence ratio of second cancers also varied according to infection type, with the highest risk among patients who had concurrent HIV. For example, in patients with DLBCL, there was a higher risk of anal cancer among patients with HIV, compared with patients with DLBCL without HIV (SIRs=68.34 vs. 2.09; p value not reported).

Age also appeared to be associated with second cancer risk, particularly liver cancer. The incidence ratio of liver cancer was higher among DLBCL patients who were diagnosed <60 years of age, compared with those diagnosed at ≥60 years of age (SIRs=2.89 vs. 1.21; p<0.01). While the incidence ratios of liver cancer following both DLBCL and MZL were higher among male patients, there were no significant differences between the sexes (SIRs in DLBCL=1.96 vs. 1.48 [p>0.5] and SIRs in MZL=2.32 vs. 1.14 [p=0.16]).

There was no elevation in risk for cervical and oropharyngeal/tonsil carcinomas among survivors of any NHL subtype. The researchers suggest this may be due to the lack of an association between NHL with human papillomavirus or populationwide screening practices.

Limitations of the study include the lack of long-term follow-up, as well as the lack of assessment of solid tumor risk due to less common subtypes of NHL. As this was a registry study, not all variables that could be risk factors for second cancers, nor therapies for infections, could be assessed. According to Dr. Morton, future studies may require more precise quantification of the magnitude of second cancer risk, considering the lack of comprehensive data of the patients’ medical histories in this study.

The authors reported no conflicts of interest.


Herr MM, Schonfeld SJ, Dores GM, et al. Risk for malignancies of infectious etiology among adult survivors of specific non-Hodgkin lymphoma subtypes. Blood Adv. 2019;3:1961-9.

This study suggests that there is a small risk of secondary solid tumors (specifically liver, gastric, and anal) among survivors of DLBCL and MZL with concurrent infections, including HIV and potentially hepatitis B, hepatitis C, and H. pylori.

There are some important caveats to this study, including the lack of longer-term follow-up beyond 10 years. Also, aside from HIV, no specific infectious etiologies were conclusively identified, nor was any mechanism for the contribution of the infection to the increased risk described.

If a shared infectious etiology influences a small increase in secondary malignancies in this population, it may suggest a rationale in screening for these infections in patients with DLBCL and MZL and treating them when found. However, it is already standard of care to evaluate patients with lymphoma for HIV and hepatitis, and patients with MZL for H. pylori. This confirms that these infections should be treated if found.

The small increase in standardized incidence ratio for most of these conditions suggests that they are rare events and does not clearly indicate a role for routine screening for secondary malignancy, except perhaps where the strongest association was seen – anal cancer risk among HIV-positive patients with DLBCL.

Catherine M. Diefenbach, MD
NYU Langone Perlmutter Cancer Center
New York, NY