Wilms Tumor is the most common pediatric renal malignancy, and the second most common abdominal solid tumor in children . There are approximately 500 new cases diagnosed in the United States each year. Due to the development of evidence-based treatment protocols and their refinement by the multidisciplinary cooperative groups over the last 40 years, long-term survival rates in Wilms tumor have dramatically improved . With these advances, a focus on refining therapy to reduce adverse effects while maintaining excellent outcomes has become increasingly important. However, an array of biomarkers that may be useful in this refinement are still lacking. Thus, new biomarker discovery could reduce both overtreatment of low-risk tumors and undertreatment of high-risk tumors, limiting unnecessary morbidity and undesired outcomes in these children.
Treatment of Wilms tumor in North America is currently based upon tumor staging, the presence of favorable or unfavorable histology, and age, using protocols developed by the Children’s Oncology Group (COG) [3, 4]. Traditionally, tumor stage has correlated closely with disease-free and overall survival . Accurate tumor staging is therefore critical to determining appropriate treatment. Stage I and II tumors are amenable to surgical resection with or without limited chemotherapy, while Stage III and IV tumors require more intensive treatment, including extended adjuvant chemotherapy regimens and in some cases, radiation therapy.
The diagnosis of stage II Wilms tumor offers a particular prognostic challenge, as these children may be at higher risk of understaging. Some authors have suggested that this depends on the number of lymph nodes sampled. In a large retrospective study, Kieran et al. found that the likelihood of finding a positive lymph node, and thus upstaging to stage III, was greater when more than 7 were sampled, suggesting that insufficient sampling may limit the accuracy of stage determination . Understaging could therefore lead to inadequate treatment of Stage III tumors, with consequent poorer outcomes [7, 8]. Stage II patients in whom lymph nodes were not sampled experienced an increase in local tumor recurrence, again associated with poorer outcomes . Consequently, there is a clear need to identify better prognostic predictors in patients with Stage II tumors.
Recently, tumor-associated macrophages (TAMs) have become the focus of significant interest for their ability to predict tumor prognosis in a number of malignancies . As cellular effectors of the innate immune system, macrophages play essential roles in a myriad of processes, including immune response, inflammation, tissue remodeling, and injury repair . Macrophages are also major constituents of tumor stroma, and an emerging body of evidence suggests that they play a prominent role in tumor growth and survival. In particular, M2 (alternatively activated) macrophages secrete anti-inflammatory cytokines, promote tissue repair/remodeling, angiogenesis, and elicit downregulation of T-cells and other immune effectors [12, 13]. Similarly, a number of experimental studies have demonstrated the ability of neoplastic cells to recruit M2 macrophages, which supports tumor growth, stimulates tumor angiogenesis, suppresses host immunity, and promotes invasion and metastasis [14, 15]. Thus, TAMs have attracted significant interest both as biomarkers and as potential targets for novel therapies .
A number of clinical studies have previously linked macrophage presence and prognosis in a variety of adult human cancers, including breast, endometrial, renal cell carcinoma, poorly differentiated thyroid cancer, and Hodgkin’s lymphoma [16–20]. In most prior reports, high numbers of macrophages have been correlated with worse prognosis, more rapid tumor progression, and decreased disease-specific survival . Consistent with these observations, tumor progression and metastasis are significantly reduced in macrophage-deficient experimental models . Taken together, these data suggest that macrophage presence might also be useful as a biomarker in pediatric solid tumors. In this study, we sought to examine the relationship between macrophage presence and clinicopathological factors in Wilms tumor.