Prognostic Significance of Tumor-Associated Macrophages in Chondroblastoma and Their Association with Response to Adjuvant Radiotherapy

Abstract

Objective: Chondroblastoma (CB) is a rare and locally growing cartilage-derived tumor. Currently, clinical implications of tumor-associated macrophages (TAMs) in CB remain unclear. In this study, we sought to analyze the relationship between TAM parameters (including densities of CD68+ and CD163+ cells as well as the CD163+/CD68+ ratio) and clinicopathological characteristics and survival of patients.

Methods: Immunohistochemistry was used to assess TAM subtypes for CD68 and CD163, as well as the expression levels of p53, CD34, and Ki-67 on tumor cells in 132 tissue specimens retrieved between July 2002 and April 2020. Then, TAM parameters were retrospectively analyzed for their associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]) and clinicopathological features.

Results: TAM densities were significantly higher in axial chondroblastoma tissue than in extra-axial chondroblastoma tissue. Moreover, the number of CD163+ TAMs was positively correlated with tumor invasion of surrounding tissues and high expression of CD34 and Ki-67 on tumor cells, whereas CD163+ cell density and the CD163/CD68 ratio were negatively associated with patient response to adjuvant radiotherapy. Univariate Kaplan-Meier analysis revealed that the number of CD68+ and CD163+ lymphocytes was significantly associated with both LRFS and OS. Multivariate Cox regression analysis showed that CD163+ and CD68+ cell levels were independent prognostic factors of LRFS, while TAM data independently predicted OS. More importantly, in subgroup analysis based on three significant factors in univariate survival analysis (including tumor location, adjuvant radiotherapy, and surrounding tissue invasion by tumors), the TAM parameters still displayed good prognostic performance.

Conclusion: These data suggest that TAM may significantly affect the biological behavior of CB. We hypothesize that modulating the TAM level or polarization status in the microenvironment may be an effective approach for CB treatment.

Keywords: chondroblastoma; prognostic factors; survival analysis; tumor immune microenvironment; tumor-associated macrophages.

Figure 1

Distribution of the tumor site for 132 chondroblastoma patients.

Figure 2

Representative images of tumor-associated macrophages parameters and immunohistochemical markers in chondroblastoma tissues.

Figure 3

The relationship between tumor-associated macrophages parameters and response to radiotherapy in patients with chondroblastoma.

Figure 4

Kaplan–Meier curves of local recurrence-free survival of chondroblastoma patients stratified by CD68+ cell density and CD163+ cell density.

Figure 5

Multivariate Cox proportional hazard analyses of prognostic factors for local recurrence-free survival in patients with chondroblastoma. The results showed that type of surgery, densities of CD163+ and CD68+ cells were significant predictors of patients’ local recurrence-free survival (bold values used in the Figure indicate P < 0.05). Patients with Enneking inappropriate tumor resection and high number of CD163+ and CD68+ cells had a 4.124-, 2.929- and 2.236-times higher risk of chondroblastoma recurrence after surgery than their counterparts, respectively.

Figure 6

Kaplan–Meier curves of overall survival of chondroblastoma patients stratified by CD68+ cell density, CD163+ cell density and CD163/CD68 ratio.

Figure 7

Multivariate Cox proportional hazard analyses of prognostic factors for overall survival in patients with chondroblastoma. The results showed that type of surgery, density of CD163+ cells and CD163/CD68 ratio were significant predictors of patients’ overall survival (bold values used in the Figure indicate P < 0.05). Patients with Enneking inappropriate tumor resection and high number of CD163+ cells had a 3.286- and 6.354-times higher risk of death after surgery than their counterparts, respectively. However, patients with low CD163/CD68 ratio within the chondroblastoma microenvironment were 0.194 times less likely to have death following surgery than those harboring high CD163/CD68 ratio.