An Increased Risk of Non-Hodgkin Lymphoma in Chronic Fatigue Syndrome Patients

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Chronic fatigue syndrome (CFS) is common in community practice and it has been speculated that it is the result of chronic immune proliferation or infection. In a review of Surveillance, Epidemiology, and End Results registry data, coupled with Medicare claims data, an association of CFS with non-Hodgkin lymphoma is clearly demonstrated.

Source: Chang CM, et al. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer 2012;118:5929-5936.

The epidemiological characterization of chronic fatigue syndrome (CFS) remains challenging due to a lack of standard disease biomarkers. Criteria established by the Centers for Disease Control and Prevention include the presence of fatigue lasting for at least 6 months, reduction in the activities of daily living, and a constellation of persistent symptoms including impaired memory, sore throat, tender lymph nodes, muscle or joint pain, and/or headache.1 This definition excludes patients with major depressive disorder, schizophrenia, alcoholism, or chronic medical conditions including autoimmune disease, cancer, and cirrhosis. Studies have estimated the prevalence in the United States to be between 0.2-0.4% and to account for more than $7 billion in medical expenses per year.2,3 CFS is more common in women, in middle age, in non-whites, and in those of middle-income status.2,3

The cause of CFS remains unknown but it is thought to be associated with chronic immune stimulation or infection. In recent years, a number of publications suggested an association of CFS with a specific retrovirus (xenotropic murine leukemia virus-related virus), but these studies most recently have been refuted.4 Nonetheless, there have been a number of studies linking CFS with chronic immunoproliferation,5,6 and as such, its association with incipient malignancy has been questioned.

To address this, Chang and colleagues performed a population-based, case-control analysis capitalizing on Surveillance, Epidemiology, and End Results (SEER) registry data of approximately 1.2 million cancer cases and 100,000 controls (age range, 66-99 years; 1992-2005). CFS was identified in the period more than 1 year prior to selection, using linked Medicare claims. Unconditional logistic regression was used to estimate the odds ratios (ORs) comparing the CFS prevalence in cases and controls, adjusting for age, sex, and selection year. All statistical tests were two-sided.

Although CFS was present at the same level in the total population of cancer patients when compared with controls (0.05%), more in-depth analysis revealed an association with non-Hodgkin lymphoma (NHL) (OR, 1.29; 95% confidence interval [CI], 1.16-1.43; P = 1.7 x 10-6). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR, 1.34; 95% CI, 1.12-1.61), marginal zone lymphoma (OR, 1.88; 95% CI, 1.38-2.57), and B cell NHL not otherwise specified (OR, 1.51; 95% CI, 1.03-2.23). CFS associations with NHL overall and NHL subtypes remained elevated after excluding patients with medical conditions related to CFS or NHL, such as autoimmune conditions (rheumatoid arthritis, Sjogren’s syndrome), hepatitis B or C, or prior transfusion. CFS also was associated, although not after multiple comparison adjustment, with cancers of the pancreas (OR, 1.25; 95% CI, 1.07-1.47), kidney (OR, 1.27; 95% CI, 1.07-1.49), breast (OR, 0.85; 95% CI, 0.74-0.98), and oral cavity and pharynx (OR, 0.70; 95% CI, 0.49-1.00).


By using SEER data linked to Medicare claims, an association of CFS with NHL was clearly demonstrated. Although other associations were demonstrated (i.e., increased risk for pancreatic and renal cancer and reduced risk for breast and oral-pharngeal cancers), these were marginal, especially when considering the level of statistical significance for NHL (P = 10-6). This confirms the findings from an earlier report7 and expands it to include NHL subtypes.

CFS is a heterogeneous disorder and diagnosis is often challenging. For those who meet diagnostic criteria, the current report demonstrates a robust association of an increased risk for lymphoma, particularly B cell NHL. By using Medicare claims data, the findings are restricted to those over the age of 65 years, whereas CFS is most common in middle age. Nonetheless, the finding is of value, both in increasing diagnostic surveillance for incipient lymphoma in CFS patients and also in providing an increased awareness of the likely link of immunoproliferative dysregulation in the pathogenesis of both disorders.


1. Prins JB, et al. Chronic fatigue syndrome. Lancet 2006;367:346-355.

2. Jason LA, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med 1999;159:2129-2137.

3. Reyes M, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003;163:1530-1536.

4. Alter HJ, et al. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio 2012;3(5). doi: 10.1128/mBio.00266-12.

5. Landay AL, et al. Chronic fatigue syndrome: Clinical condition associated with immune activation. Lancet 1991;338:707-712.

6. Racciatti D, et al. Study of immune alterations in patients with chronic fatigue syndrome with different etiologies. Int J Immunopathol Pharmacol 2004;17(2 Suppl):57-62.

7. Levine PH, et al. Cancer and a fatiguing illness in Northern Nevada — a causal hypothesis. Ann Epidemiol 1998;8:245-249.