Risk of Second Lung Cancer in Chronic Lymphocytic Leukemia.
Authors: Schoellkopf Claudia , Rosendahl Ditte , Pipper Christian , Hjalgrim Henrik 
Published: October 2019

Abstract
Background: Studies have shown that patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing second lung cancer. The underlying mechanisms for this increased risk have yet not been identified. Risk factors may differ between histological lung cancer subtypes. However, though relevant to the clarification of the association between the two malignancies, little is known about the lung cancer subtype distribution in CLL patients.
Methods: We investigated the occurrence of second lung cancer overall and its major histological subtypes in all patients diagnosed with CLL in Denmark between 1943 and 1999 in a retrospective registry-based cohort study. The relative risk was expressed as the standardized incidence ratio (SIR), i.e. the ratio of the observed to the expected number of lung cancer cases, based on age-, sex-, and calendar year specific incidence rates for the Danish population, available from the Danish Cancer Registry.
Results: Overall, 9,541 patients diagnosed with CLL between 1943 and 1999 were followed for lung cancer occurrence. The median age at onset was 70 years and the male-to-female ratio was 1.6. Second lung cancer occurred in 147 patients (122 men and 25 women) during 36,604 person-years of follow-up (median 2.5 years) corresponding to a statistically significantly increased relative risk (SIR=1.83, 95% CI 1.55–2.15). There was no difference in risk between women and men (phom=0.27). The relative risk for lung cancer varied slightly by age at CLL being particularly high in younger age groups (≤59 years SIR=2.18 (1.53–3.10), 60–69 years SIR=2.26 (1.78–2.86), 70–79 years SIR=1.28 (0.93–1.76), ≥80 years SIR=1.51 (0.79–2.90); phom=0.02). In contrast, SIR for lung cancer did not vary by time since CLL diagnosis (phom=0.64). In 95 cases (72 men, 23 women) of second lung cancer information about major histological subtypes were available. We found a statistically significantly elevated risk for all major subtypes, except small-cell carcinoma (adenocarcinoma SIR=2.85 (2.04–3.99), large-cell carcinoma SIR=2.31 (1.04–5.15), squamous cell carcinoma SIR=2.30 (1.68–3.14), small cell carcinoma SIR=1.47 (0.90–2.39)).
Discussion: In one of the largest and most detailed register-based cohort studies so far, we found an increased occurrence of lung cancer among CLL patients, which was apparent for major lung cancer subtypes. While increased medical surveillance of the CLL patients cannot be ruled out as explanation for the increased risk, the uniform distribution over time since CLL diagnosis suggests that it is unrelated to initial therapy. Tobacco smoking is the major risk factor in lung cancer. Data on smoking history were not available in our study, however, previous studies suggest that smoking is not associated with CLL. Family aggregation found for both lung cancer and CLL may indicate hereditary predisposition to the two conditions. Furthermore, individual susceptibility to malignant diseases may be influenced by polymorphisms in enzymes metabolizing carcinogenes, suggested independently for CLL and lung cancer. Given the prolonged survival of patients with CLL, further studies are needed to address the causal relationship between CLL and second malignancies, including lung cancer.