High Expression of Parathyroid Hormone-related Protein and Tumor Necrosis Factor-α in Cancer Cells as Risk Factors for Hypercalcemia in Bone Metastases Lytic Lesions

Abstract

BACKGROUND: Cancer mortality is more commonly due to metastases of the tumor to other organs and the complications that accompany it than the tumor growth itself. Until recently, metastasis has been an insurmountable problem. AIM: As the most frequent site of metastases, apart from the lungs and liver, tumor metastases to bone are associated with hypercalcemia which is fatal for the affected patient. METHODS: This study used a case-control study design. The case group consisted of paraffin block samples derived from bone metastatic cancer cell biopsies of patients with hypercalcemic lytic lesions. The control group consisted of paraffin block samples derived from bone metastatic cancer cell biopsies of patients with non-hypercalcemic lytic lesions. Radiological examination was performed to examine the presence of lytic lesions, followed by data collection of serum calcium levels. The data obtained from the histopathological examination was confirmed along with the availability of paraffin blocks of bone metastasis cancer cell biopsy samples, and immunohistochemical analysis was performed to determine the expression of tumor necrosis factor-α _(TNF-α) and parathyroid hormone-related protein (PTHrP). A Mann–Whitney test was performed to determine the expression of TNF-α _and PTHrP between hypercalcemia and non-hypercalcemia groups. To identify the cut-off point, Youden index on receiver operating characteristic was used, then the optimal cut-off point was determined where the sensitivity and specificity curves intersect. Analysis of risk factor assessment was done by creating a 2 × 2 cross-tabulations and calculating the association size in the form of odds ratio (OR). RESULTS: The expression of PTHrP and TNF-α _in the case group was significantly different from the control group with p < 0.05. The cut-off point for PTHrP expression was 267.5 with an area under the curve of 0.93, indicating a high accuracy value. The cut-off point for TNF-α _expression was 227.5 with an area under the curve of 0.68, indicating a moderate accuracy value. The OR between hypercalcemia and non-hypercalcemia to PTHrP expression was 110.3 (Fisher’s exact statistical test obtained p < 0.05), while the OR between hypercalcemia and non-hypercalcemia to TNF-α _expression was 7.27 (Fisher’s exact test statistical obtained p = 0.01). CONCLUSION: Significant differences in the expression of PTHrP and TNF-α _were found between patients with bone metastases lytic lesions with hypercalcemia compared to those without hypercalcemia. We can conclude that either a high level of PTHrP expression and/or TNF-α _expression in cancer cells can serve as risk factors for hypercalcemia in patients with bone metastatic lytic lesions.