Hepatoma-derived growth factor expression as a prognostic marker in cervical cancer

AIM： To examine the association of hepatoma-derived growth factor （HDGF） expression with the prognosis of patients with cervical cancer of the uterus （CC）. METHODS： HDGF is a unique nuclear growth factor, and it may play an important role in the development and progression of carcinoma. HDGF expression in 88 CC patients aged 23 to 76 years （median, 54 years） was analyzed by immunohistochemistry. A rabbit polyclonal antibody against the C-terminal amino acids （aa 231-240） of the human HDGF sequence was used as primary antibody at a dilution of 1：5000. This specific anti-HDGF antibody was purified using C-terminal peptide-conjugated Sepharose columns. Staining of endothelial cells in the noncancerous areas of each specimen was used as an internal positive control. Samples with more than 80% of tumor cells showing positive immunoreactivity in both the nucleus and cytoplasm were regarded as HDGF index level 2,more than 80% positive immunoreactivity in either the nucleus or cytoplasm as level 1, and less than 80% in both the nucleus and cytoplasm as level 0. The chi-square test and Fisher’s exact probability test were used to examine the relationship between HDGF expression and clinicopathologic parameters, and statistical significance was examined by the log-rank test. Multivariate analysis of factors related to survival was performed using Cox’s proportional hazards regression model. Statistical signifcance was set at P 〈 0.05. RESULTS： The five-year overall survival rate was 82.9%. Fourteen patients died due to tumors, nine of whom had tumor recurrence at 2-21 mo （median, 10 mo） after surgery. Tumor recurrence in five patients was determined at the time of the patients’ deaths. Nineteen cases were regarded as HDGF index level 0, 11 as level 1, and 58 as level 2. Patients with level 2 expression showed higher rates of histological classification of keratinized squamous cell carcinomaand adenosquamous carcinoma （44.8% of level 2 patients and 13.3% in levels 0 and 1）, deep invasion （pT2-4 in 65.5% of level 2 patients, and 30.0% in levels 0 and 1）, the presence of lymphatic invasion （50.0% in level 2, and 20.0% in levels 0 and 1）, and the presence of lymph node metastasis （37.9% in level 2, and 6.7% in levels 0 and 1）. Patients with an HDGF index of level 2 CC showed poorer 5-year overall survival rates than those with level 0 or 1 CC （74.0% and 100%, respectively, P = 0.0036）. Univariate analysis revealed that histological classification （P = 0.04）, depth of tumor invasion （P = 0.0001）, vascular invasion （P = 0.004）, and lymph node metastasis （ P = 0.0001） were significant factors affecting overall survival in addition to HDGF expression. Multivariate analysis revealed HDGF expression level and lymph node metastasis as independent prognostic factors for overall survival （P = 0.0148 and P = 0.0197, respectively）. The prognostic signifcance of HDGF was further analyzed in pT1 andsignifcance of HDGF was further analyzed in pT1 and pT2-4 patient groups, respectively. Among patients with pT1 CC, one the 39 analyzed patients died during the study, and no difference was observed among patients with HDGF index level 0, 1, or 2 CC. However, prognostic signifcance of the HDGF index was observed in the pT2-4 patient group, in which the mortality rates of patients with HDGF index level 2 CC and those with level 0 or 1 CC signifcantly differed （P = 0.0463）. CONCLUSION： The HDGF expression level is of prognostic signifcance in CC.

AIM: To examine the association of hepatoma-derived growth factor(HDGF) expression with the prognosis of patients with cervical cancer of the uterus(CC). METHODS: HDGF is a unique nuclear growth factor, and it may play an important role in the development and progression of carcinoma. HDGF expression in 88 CC patients aged 23 to 76 years(median, 54 years) was analyzed by immunohistochemistry. A rabbit polyclonal antibody against the C-terminal amino acids(aa 231-240) of the human HDGF sequence was used as primary antibody at a dilution of 1:5000. This specific anti-HDGF antibody was purified using C-terminal peptide-conjugated Sepharose columns. Staining of endothelial cells in the noncancerous areas of each specimen was used as an internal positive control. Samples with more than 80% of tumor cells showing positive immunoreactivity in both the nucleus and cytoplasm were regarded as HDGF index level 2, more than 80% positive immunoreactivity in either the nucleus or cytoplasm as level 1, and less than 80% in both the nucleus and cytoplasm as level 0. The chisquare test and Fisher's exact probability test were used to examine the relationship between HDGF expression and clinicopathologic parameters, and statistical significance was examined by the log-rank test. Multivariate analysis of factors related to survival was performed using Cox's proportional hazards regression model. Statistical significance was set at P < 0.05. RESULTS: The five-year overall survival rate was 82.9%. Fourteen patients died due to tumors, nine of whom had tumor recurrence at 2-21 mo(median, 10 mo) after surgery. Tumor recurrence in five patients was determined at the time of the patients' deaths. Nineteen cases were regarded as HDGF index level 0, 11 as level 1, and 58 as level 2. Patients with level 2 expression showed higher rates of histological classification of keratinized squamous cell carcinomaand adenosquamous carcinoma(44.8% of level 2 patients and 13.3% in levels 0 and 1), deep invasion(p T2-4 in 65.5% of level 2 patients, and 30.0% in levels 0 and 1), the presence of lymphatic invasion(50.0% in level 2, and 20.0% in levels 0 and 1), and the presence of lymph node metastasis(37.9% in level 2, and 6.7% in levels 0 and 1). Patients with an HDGF index of level 2 CC showed poorer 5-year overall survival rates than those with level 0 or 1 CC(74.0% and 100%, respectively, P = 0.0036). Univariate analysis revealed that histological classification(P = 0.04), depth of tumor invasion(P = 0.0001), vascular invasion(P = 0.004), and lymph node metastasis(P = 0.0001) were significant factors affecting overall survival in addition to HDGF expression. Multivariate analysis revealed HDGF expression level and lymph node metastasis as independent prognostic factors for overall survival(P = 0.0148 and P = 0.0197, respectively). The prognostic significance of HDGF was further analyzed in p T1 and p T2-4 patient groups, respectively. Among patients with p T1 CC, one the 39 analyzed patients died during the study, and no difference was observed among patients with HDGF index level 0, 1, or 2 CC. However, prognostic significance of the HDGF index was observed in the p T2-4 patient group, in which the mortality rates of patients with HDGF index level 2 CC and those with level 0 or 1 CC significantly differed(P = 0.0463). CONCLUSION: The HDGF expression level is of prognostic significance in CC.