Elevated White Blood Cell Counts May Signal Higher Cancer Risk

Roxanne Nelson
October 1, 2007 — Postmenopausal women with elevated white blood cell (WBC) counts appear to be at a higher risk of developing certain malignancies, including incident invasive breast, colorectal, endometrial, and lung cancers. The study, which appears in the September 24 issue of the Archives of Internal Medicine, also found that higher levels of WBCs in this population conferred a higher risk of breast, lung, and overall cancer mortality.
"The mechanisms through which inflammation leads to carcinogenesis are incompletely understood," write Hemant K. Roy, MD, and Janardan D. Khandekar, MD, from Evanston Hospital in Illinois, in an accompanying editorial. "Most of the attention in carcinogenesis has focused on adaptive immunity, especially derangements in humoral and cell-mediated immunity."
However, they note, the role of the innate immune system, which includes WBCs, is just beginning to be explored, and recent data demonstrate that in the presence of precancerous tissue, leukocyte antibody receptors become activated and might serve as signals for both growth factors and angiogenesis.
"These findings suggest that leukocytes may be involved in the progression phases of carcinogenesis," they write. "Therefore, it is biologically plausible that WBCs may be involved in cancer development."
However, the editorialists point out that even though the study authors found it statistically significant, the correlation between the WBC count and cancer risk was weak. However, although a WBC count is clearly inadequate for cancer detection, they note, this paper presents compelling support for inflammation as a biomarker.
"The observation that the peripheral WBC count appears to be inadequate for cancer screening does not diminish the promise of probing the immune system," and "this finding foreshadows the use of more sophisticated technologies to exploit the inflammation-cancer link," write Drs. Roy and Khandekar.
Considering the fact that it is an inexpensive test commonly used in clinical practice, the WBC count has been surprisingly infrequently evaluated in epidemiologic studies, explained senior author Karen Margolis, MD, MPH, a senior clinical investigator at HealthPartners Research Foundation, in Minneapolis, Minnesota. "One problem is that it has to be measured right away, whereas many other biomarkers can be measured in stored specimens."
Dr. Margolis and colleagues sought to determine whether there is an independent association between WBC count and incident cancer in postmenopausal women. Their analysis included data on 143,748 postmenopausal women enrolled in the Women's Health Initiative (WHI). At baseline, between 1993 and 1998, the women were between the ages of 50 and 79 years and were free of cancer.
"What the WHI data brings to this topic is the ability to look at cancer incidence and not just cancer mortality, and to compare the association with several types of incident cancer," Dr. Margolis told Medscape Oncology. "The large size of WHI allows us to find relatively small effect sizes."
Upon examining patient demographics, the researchers observed that higher WBC counts were associated with factors that included older age, current tobacco use, aspirin use, higher parity, hypertension, diabetes mellitus, current use of hormones, and a greater body mass index. Conversely, lower counts were associated with factors such as physical activity, months of breastfeeding, increased alcohol use, and ethnic background.
When the analysis was adjusted for age, they noted a graded association between WBC count and incident invasive breast cancer (4639 cases), colorectal cancer (1341 cases), endometrial cancer (766 cases), and lung cancer (1237 cases). After adjustment for possible confounders, the strength of the associations was lessened, but the significant trends with increasing WBC quartile remained.
Women in the highest quartile of WBC count (6.80-15.00 x 109 cells/L) had a 15% higher risk for invasive breast cancer, a 19% higher risk for colorectal cancer, a 42% higher risk for endometrial cancer, and a 63% higher risk for lung cancer than patients in the lowest quartile of WBC count (2.50-4.79 x 109 cells/L).
The results were similar when cancers that developed during the first 2 years of follow-up were excluded from the data. When current smokers were removed from the multivariate analyses, the association between WBC count and invasive breast cancer and endometrial cancer was almost identical. However, the association with colorectal cancer was weaker and statistically nonsignificant.
The researchers also found that there was a strong association between WBC count and mortality related to invasive breast cancer and lung cancer, and between WBC count and overall death from cancer. Even after age and multivariate adjustments, the incidence of mortality from invasive breast cancer remained more than 2 times higher among patients in the highest WBC quartile. Age-adjusted analysis for lung cancer mortality showed a more than 3-fold risk for women in the highest WBC quartile, although after adjustment for smoking, the association was weakened. However, the relationship was still statistically significant, showing a 65% increase in lung cancer mortality in the highest WBC quartile.
Although previous studies have shown mixed results, the preponderance of the evidence was in favor of an association between WBC and cancer before the publication of this study, said Dr. Margolis, and between WBC and C-reactive protein.
"I think the results are likely to apply to men and younger populations, keeping in mind that cancer rates generally go up quite steeply with age," she said. "Younger populations are harder to study."
Although the results of this study are not ready to be applied clinically, physicians should take note of an elevated WBC, even one in the upper range of normal, Dr. Margolis pointed out. "I do think a WBC in the upper range of normal — above 7 or so — should be on clinicians' radar, especially if it is persistent and unrelated to any known cause."
"Of course," she added, "Most people with a WBC in this range will not develop cancer or cardiovascular disease in the next 5 to 10 years, and the relative risk increase for cancer is quite small."
The WHI program is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services.
Arch Intern Med. 2007;167(17):1837-1844, 1822-1823