So far, a group of original articles and reviews has studied the prognostic significance of TAM in solid tumors, and the presence of both significant and non-significant studies addressing the importance of TAM on survival made it necessary to perform a quantitative aggregation of the survival results. The present result showed that high density of TAM, as detected with immunohistochemistry, was significant associated with worse overall survival in solid tumor, with a global RR of 1.15. As potential bias exists between studies on different tumors, subgroup analysis was also performed, which suggested that high density of TAM was significant associated with OS in patients with gastric cancer [RR
1.64 (95%CI, 1.24–2.16)], breast cancer [RR
8.62 (95%CI, 3.10–23.95)], bladder caner [RR
5.00 (95%CI, 1.98–12.63)], ovarian cancer [RR
2.55 (95%CI, 1.60–4.06)], oral cancer [RR
2.03 (95%CI, 1.47–2.80)] and thyroid cancer [RR
2.72 (95%CI, 1.26–5.86)]. Moreover, there showed positive effect in patients with colorectal cancer [RR
0.64 (95%CI, 0.43–0.96)]. However, no significant effect was seen between TAM and DFS.
When comparing the results of different types of tumors, several key differences were observed. As mentioned above, although macrophages under certain conditions can kill tumor cells, they can also play potential roles as tumor promoters to secrete a variety of factors that directly stimulate tumor invasion and metastasis. The combing effect of TAM on prognosis in patients with different tumors depends on stimulating factors from two opposite aspects in tumor environments. In this meta-analysis, we reach a conclusion that high TAM infiltration is associated with worsen prognosis in patients with urogenital cancer or gastric cancer, not all cancer type. In other hand, TAM showed antitumorigenic properties in combing 5 studies on colorectal cancer, resulting in improved prognosis.
To further investigate the prognostic value of TAM in different type of cancer, we analyzed the relation between the density of TAM and clinic-pathological factors that was also associated with outcome of cancer patients. As the density of TAM has a negative effect on survival in patients with gastric cancer, breast cancer, bladder cancer, ovary cancer, and oral squamous cell carcinoma, negative effects are also seen in clinic-pathological factors such as TNM staging (breast cancer, bladder cancer and oral squamous cell carcinoma), T status (breast cancer and oral squamous cell carcinoma), lymph node metastasis (breast cancer, bladder cancer and oral squamous cell carcinoma), and distant metastasis (bladder cancer), which contributed to tumor progression and patient survival. Interestingly, there also demonstrated a positive effect of TAM on lymph node metastasis in gastric and ovary cancer, which indicated that high density of TAM was associated with less probability of lymph node metastasis, however, significant negative effect was shown on overall survival. Thus, more studies are needed to clarify this ambivalent phenomenon. Contrary to tumors we mentioned above, our data suggested that an incremental increase in density of TAM improved overall survival in patients with colon cancer, with a homodromous effect on T status. There was also a trend towards lower rate of lymph node metastasis and distant metastasis in TAM rich tumors. In addition, a high density of TAM infiltration was found related to nonmucious type of colon cancer.
The mechanisms behind the oncogenic and anti-tumorigenic effects of TAMs have not been fully elucidated and a great number of studies have focused on explaining these apparently contradictory effects of TAM in different cancer outcome. The functions of TAM in different type of tumors are concerned as the most important determining factor to the prognosis, which are profoundly affected by microenvironmental signals and can range from powerful stimulation of inflammatory responses to induction of immunosuppression 
. Tumor necrosis factor (TNF)-α, nitric oxide (NO), and monocyte chemoattractant protein (MCP)-1 released from TAM are major intermediate molecules for tumor cell killing 
, and TAM associated vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are independent predictor of poor prognostic factor in cancer patients 
. In addition, a macrophage balance hypothesis between M1 and M2 type macrophages has been proposed and two different macrophage populations range from polarized potent killer M1 cells to alternatively activated M2 macrophages with tumor-promoting capability 
. However, this study showed no significant relation between the density of two phenotype of TAM and survival of patients. Furthermore, histological classification of the tumor should also be considered as a factor correlated with the function of TAM. A previous study on colon cancer demonstrated that a histologically more malignant phenotype was associated with macrophage infiltration, disorganized matrix deposition, and extensive stromal reaction 
. In one included study of this meta-analysis, the number of infiltrating TAM was found to be significantly correlated with poor outcome in patients with intestinal type of gastric cancer, but not in patients with diffuse type, indicating that TAM could affect malignant progression and prognosis on the basis of the histological type of gastric cancer 
Although the results of meta-analysis are considered as gold standards by authors worldwide 
, potential bias still exists between studies and cannot be completely eliminated. Although Begg's funnel plot and Egger's test were performed in this meta-analysis and found no statistically significant publication bias, results of this study should be interpreted very cautiously and several aspects of importance in this field should be discussed. First of all, we only included studies from which we could extract RR or estimate RR, leading to data inaccessible for data aggregation from studies, which only showed the conclusion on this topic without data presented. Take one excluded study on evaluating the prognostic value of TAM on oral cavity and oropharyngeal squamous cell carcinoma for example, they found that macrophage content was an independent predictor of lymph node metastasis, however, no data was accessible for meta-analysis from this study 
. Furthermore, considerable attention should be paid to some cancers with few study included in this meta-analysis study. TAM was found associated with worse prognosis in one study on oral cancer [RR
2.03 (95%CI, 1.47–2.80)] 
and one study on thyroid cancer [RR
2.72 (95%CI, 1.26–5.86)] 
. As meta-analysis could not be performed with such small number of primary studies, more researches are needed in further investigation on these tumors.
Second, macrophages can be identified by cell surface markers, expression of transcriptional factors, the production of cytokines and their functions in vitro 
. However, we only included literatures evaluating TAM with the use of antibodies to the glycoprotein CD68. Sikert et al quantified TAM by immunohistochemistry with antibodies to PG-M1, KP-1, MRP8, MRP14 and MRP8/14 antigens and found different TAM subpopulation were positively correlated with clinicopathological characteristics in colon cancer 
. Macrophage differentiation, growth, and chemotaxis are regulated by several growth factors, including colony-stimulating factor (CSF)-1, macrophage chemoattractant protein (MCP)-1 and extracellular matrix protease such as urokinase-type plasminogen activator (uPA) 
. For example, over expression of CSF is associated with poor prognosis in nongynecological leiomyosarcoma 
. In breast cancer, TAM density is showed correlated with angiogenesis and poor prognosis 
. Ohba et al provide the evidence that uPA has prognostic value in patients with renal cell carcinoma via TAM 
. Also other factors could be used to evaluate M1 and M2 type macrophages in tumor tissues. As M2 type TAM express high level of interleukin-10 (IL-10) which can be used to discriminate between M1 and M2 macrophages 
, a study assessed IL-10 expression in TAM, and found the high level of IL-10 in TAM significantly correlated with clinical staging and histologic poor differentiation in patients with lung cancer 
. So, considerable attention should be paid to various kinds of factors related to density of TAM, which might be a potential prognostic marker in solid tumor.
Third, variability in definitions, outcomes, measurements, experimental procedure, and even antibody concentration may contribute to heterogeneity between studies 
. Multivariate analyses was tried to minimize confounding bias, but the factors controlled for were few and differed between studies. Quality criteria are needed for future studies in this field, and we make the following recommendation: blindly assess the prognostic marker to patient outcome, adequately describe the assay method used for TAM evaluation including antibody concentration and cut-off value staining for TAM high, and precisely define outcome with certain follow-up time. More importantly, in this meta-analysis, some studies have used 20% as the cutoff value, whereas others have chosen score system, mean, median or arbitrary cutoff values, thus cutoff value is a source of considerable interstudy heterogeneity. Although specific synthesis of studies using standardized cutoff value on survival did not differ significantly form the overall result in the total population analysis, conclusions need to be considered cautiously.
In conclusion, it is clear that TAM has protumorigenic as well as antitumorigenic properties in solid tumor. As discussed above, there have been showed a “macrophage balance” on prognosis depending on the microenvironment of the tumor tissue in different type of solid tumor. It may be possible in the future to use or induce activated macrophages to restrain tumor growth and improve patient survival, through altering tumor microenvironment. Moreover, targeted therapies that uniquely strike macrophages may provide innovative therapeutic strategies against tumor progression.