Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy
Introduction
Breast cancer diagnosis is a time of considerable uncertainty, anxiety, and emotional distress (Northouse et al., 1995; Deane and Degner, 1998; Stark and House, 2000). This emotional experience often begins with the discovery of clinical or radiographic findings that indicate the need for biopsy of the breast (Benedict et al., 1994). Breast biopsy, either by surgical excision or by less invasive procedures, provides for the pathological evaluation and diagnosis of a suspicious breast abnormality. Despite knowing that the large majority of women undergoing breast biopsy have benign results (Ghosh et al., 2005), anticipating a breast biopsy and experiencing the concomitant uncertainty and fear of a cancer diagnosis, is emotionally disturbing (Nagabhushan et al., 2001; O’Mahony, 2001; Montgomery et al., 2003). Women express high levels of anxiety after the discovery of a breast lump (MacFarlane and Sony, 1992) and at the time of biopsy they report higher levels of stress compared to patients awaiting general surgery (Hughson et al., 1988). The impact of psychological stress and anxiety is not limited to central nervous system activation but has repercussions for numerous biological systems, including the immune system. Reciprocal neuro-chemical pathways and shared receptor systems connect the nervous, endocrine, and immune systems as a network (Madden and Felten, 1995; Weigent and Blalock, 1999; Charmandari et al., 2005). This intricate neuro-endocrine-immune network provides the link whereby perceived environmental stressors or demands, such as undergoing biopsy of the breast, may effect the immune system and influence health status (Andersen et al., 1994; Witek-Janusek and Mathews, 2000; Glaser, 2005).
A large body of evidence supports the assertion that psychological stress can adversely affect the human immune response (Biondi, 2001; Glaser, 2005). Stress-induced immunosuppression accompanies a variety of acute and chronic life stressors such as bereavement (Irwin et al., 1987), depression (Weisse, 1992), marital conflict (Kiecolt-Glaser et al., 1993), academic exam stress (Kiecolt-Glaser et al., 1986), and care giving in chronic disease (Kiecolt-Glaser et al., 1987). A relationship between stress and natural killer cell activity (NKCA) has been suggested for some time (Trinchieri, 1989). Andersen et al. (1998) demonstrated stress-induced immune alterations in women newly diagnosed with invasive breast cancer (Stage II and III). These women were evaluated within 4 months of their breast surgery but prior to adjuvant therapy initiation. The results of that study showed that higher stress levels were predictive of lower NKCA, diminished natural killer (NK) cell response to interferon (IFN), and decreased lymphocyte proliferation (Andersen et al., 1998). It is possible that stress may influence cancer control. Although a direct relationship between NKCA and cancer has not been clearly established, patients with a variety of solid tumors (e.g., breast, cervix, endometrium, ovary, and lung) do exhibit reduced NKCA (Pross and Lotzova, 1993). More recent investigations with gene-depleted mice, provide evidence that NK cells mediate protection from tumors (Diefenbach and Raulet, 2002) including; initiation (van den Broek et al., 1996; Street et al., 2001), primary tumor growth (van den Broek et al., 1996), and tumor metastasis (Zhang et al., 1999; Street et al., 2001).
The effects of stress upon the immune system extend not just to NK cells but also to the peripheral blood cell production of cytokines. Heightened levels of stress have been related to decreased synthesis of IFN γ (Kiecolt-Glaser et al., 1986) and a poorer NK response to IFN and IL-2 (Esterling et al., 1994, Esterling et al., 1996). Posttraumatic stress disorder (Maes et al., 1999) and academic exam stress (Marshall et al., 1998) are reported to lead to cytokine dysregulation. Moreover, interventions that reduce stress can modulate NKCA and cytokine responsiveness (Esterling et al., 1994), suggesting an interactive relationship between stress and NK function, that may be mediated by cytokines (Esterling et al., 1996). The cytokine response to stress can be triggered by changes in adrenal hormone production (McEwen et al., 1997; Elenkov and Chrousos, 2002), in that cortisol secreted during stress, can switch a Th1 to a Th2 immune response (Daynes et al., 1990; Rook et al., 1994; Elenkov, 2004). Such a switch in cytokine balance, characterized by low levels of IFN γ, can depress NK cell function (Targan and Dorey, 1980; Reiter, 1993; Biron et al., 1999).
The purpose of this study was to evaluate the psychological impact of the breast biopsy experience and to determine whether this experience was accompanied by changes in NKCA and cytokine production. The experience of breast biopsy represents a naturalistic human paradigm known to be characterized by uncertainty, mood disturbance and emotional distress (Nagabhushan et al., 2001; O’Mahony, 2001; Montgomery et al., 2003). As such this paradigm can be used to understand potential links between a woman's psychological and immunological states. In this study, psychological stress and immune response were measured before and after breast biopsy and compared to a group of control women not undergoing breast biopsy.
Section snippets
Subjects and procedure
Women, over 21 years of age, who were recommended for breast biopsy were eligible subjects. Breast biopsy comprised any surgical biopsy or image-guided core-needle biopsy (including stereotactic or ultrasound guided) carried out on the breast for the purpose of diagnosis; women receiving fine needle aspirates of the breast were excluded. Other exclusionary criteria were: pregnancy, recent history of major psychiatric disorder, concurrent major immune-based disease, use of immune-altering
Demographic characteristics of study participants
Table 1 summarizes the demographic characteristics of all study women. As expected women with malignant findings were somewhat older (60.3±2.2 years, X±SE) compared to women with benign biopsy results (50.1±1.5 years). Likely due to their older age, fewer of the women with malignancy were married or employed at study entry. Respectively, 85%, 89%, and 93% of the Benign, Malignant, and Comparison (Control) group women were Caucasian. The only Hispanic women (3%) who participated in the study
Discussion
Suspicious breast findings that require evaluation by biopsy herald the onset of an emotional experience that is often accompanied by uncertainty and fear of a cancer diagnosis (Benedict et al., 1994; Northouse et al., 1995; Deane and Degner, 1998). For most women, the unfolding of this emotional scenario occurs over a period of several weeks, from the time of discovery of questionable breast findings, through the scheduling and conduct of the biopsy, and finally to the time that the biopsy
Acknowledgements
The study was supported in part by: National Cancer Institute CA-77120, the Department of the Army DAMD 98-8120, the Cancer Federation, the Loyola University School of Nursing Palmer Research Fund, and the Loyola University Summer Stipend Program. The content of this manuscript does not reflect the position or the policy of the Department of the Army or the government. Our heartfelt thanks are extended to all the women who so graciously agreed to participate in this study. The authors
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