Consistent with the NCI consensus statement, pain, fatigue and depression independently, as well as a symptom cluster, were found to be prevalent in people diagnosed with hepatobiliary carcinoma, with approximately 25% of patients experiencing high levels of pain, depression, and fatigue, and another 35% of patients reporting persistent fatigue. Overall, the three symptoms were reported in 62–85% of patients from diagnosis to six-month follow-up.
Although research has been conducted regarding the association of cancer-related symptoms and cytokines, no study has investigated the association between cancer-related symptoms and eosinophils, which may have a significant role in the context of cancer. The high level of cancer-related symptoms and association with eosinophils could not be accounted for by comorbid diseases that are established as being associated with eosinophilia (e.g., allergy, asthma).
Prospectively, pain was associated with higher percentages of eosinophils both at three-and six-month follow-ups. Eosinophils are multifunctional leukocytes that are involved in numerous inflammatory processes across disease types. Eosinophils, independent of other subtypes of leukocytes, can be recruited from the circulation into inflammatory areas of the body, and modulate immune responses through various mechanisms, including antigen presentation and release of cytokines IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, RANTES and eotaxin-1. Activation and recruitment of eosinophils may regulate vascular permeability and smooth muscle constriction. In addition, eosinophils may serve as a major effector cell, inducing tissue damage by releasing toxic granule proteins.
Our finding are consistent with reports of hypereosinophila outside the context of cancer. Eosinophilia has been associated with upper quadrant pain and fatigue (68
), and is hypothesized to be associated with necrotic cell death, particularly during periods of nutrient, hypoxic, and oxidant stress (29
). Although a trend toward significance was found in regard to depressive symptoms and eosinophilia over time, fatigue was not found to be associated with eosinophil percentage secondary to the lack of inter-individual variability in the report of fatigue over time.
The link between pain and eosinophils is believed to result from a cascade of events, possibly including increased tissue temperature caused by the release of histamines, which stimulate pain-sensing neurons. This may be followed by an increase in capillary permeability, resulting in the migration of leukocytes and macrophages from the circulatory system to the damaged tissue (69
). As a result of the increased leukocytes and macrophages migrating into the tissue, edema and white blood cell body remnants, which increase the cellular pressure, may result in the sensation of pain (69
In the setting of cancer, pain is often thought to be associated with tumor burden, which may also be indicative of decreased survival. However, post-hoc analyses were performed and pain at diagnosis, as well as at three- and six-month follow-ups, found that pain was not related to tumor size or survival. Prior studies have found that elevations in eosinophils were associated with cirrhosis (70
). However, posthoc analyses revealed a lack of association between cirrhosis and eosinophil levels in the present study.
Tumor-associated blood eosinophilia in the present study, as well as previous studies of solid organ tumors, is consistent with a favorable prognosis for people diagnosed with hepatobiliary carcinoma. Although the pathogenesis of eosinophilia is not well understood, necrosis of the tumor has been hypothesized as a possible etiology of eosinophilia (29
). Although TATE and TABE often occur independently, TABE is more often observed in advanced disease or metastatic disease (31
Eosinophilia has been observed in a number of disease processes, most notably allergy and parasitic infection (29
); therefore, the elevations in eosinophils could be related to comorbid diseases rather than the tumor cell death. Although random assignment, which would control for the influence of comorbid medical conditions that may be correlated with eosinophilia, was not the design of this study, post-hoc analyses found no association between eosinophil levels and comorbid disease processes.
Although this is a rather new area of investigation, we did not expect that other leukocyte subsets would necessarily be associated with symptoms or survival. Even though basophils are associated with inflammatory reactions, these granulocytes are specifically associated with allergic reactions or exoparasitic infections and therefore did not expect elevations or associations in this subset. While we did expect neutrophils, and in particular, neutropenia, to be associated with fatigue, secondary to the lack of variability over time and between clusters, an association could not be detected.
A limitation of the present study included the use of single item measures of pain, fatigue, and depression was used for the purposes of this study. However, in a subsample of patients, these single items were found to be highly correlated with multidimensional instruments such as the Center for Epidemiological Studies-Depression scale, Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Fatigue scale.
Although we did assess other symptoms and side effects of treatment (e.g., nausea and vomiting, itching, fevers), the frequency of these symptoms was low (<10%) and thus we did not include these symptoms in the analyses. Future research should include multidimensional instruments designed to measure each symptom to better understand the “multiplicative” or catalytic effects of symptoms on one another and the use of multilevel factor analysis (3
The present study provides preliminary support regarding the co-occurrence of cancer-related symptoms and the association between these symptoms, biomarkers, and disease progression. However, cellular infiltration of eosinophils (e.g., TATE) should also be studied in patients with hepatobiliary carcinoma to provide further evidence of the role of tumor-associated tissue eosinophilia in disease progression. Furthermore, the cytokine-immunological model of cancer-related symptoms warrants testing based on the results of this study. Understanding the link between cancer-related symptoms, immunity, and disease progression may contribute to the development of pharmacological interventions to facilitate the management of cancer-related symptoms and potentially slow disease progression in solid tumor cancers.