Study on the overexpression of succinate dehydrogenase B and MIB-1 in pheochromocytoma/paraganglioma tissue

Abstract

Objective We aimed to investigate the overexpression of succinic dehydrogenase (SDH)B and MIB-1 in patients with pheochromocytoma/paraganglioma(PHEO/PGLs) and its significance for predicting the clinical malignant behavior. Methods From August 2008 to April 2016, the clinical characteristics of 93 patients with PHEO/PGLs were analyzed retrospectively. There were 57 males and 36 females. with an average of 34 years, ranging 8-73 years old. There were 68 cases of adrenal pheochromocytoma and 25 cases of paraganglioma. There were 79 cases with hypertension and 14 cases of adrenal accidental tumors. Sixty-six cases with typical hyper-catecholamine secretion symptoms and 27 cases with non-functional PHEO/PGL. Benign PHEO/PGLs were 77 cases and malignant 16 cases. The tumor was located on the left side in 39 cases, on the right side in 32 cases and multiple lesions in 22 cases. The diameter of the PHEO/PGL tumor was (6.8±2.7) cm. The 24 h urine catecholamine was measured before operation, which showed epinephrine was(42.6±5.1)μg/24 h, norepinephrine was(167.5±13.5)μg/24h and dopamine was (246.4±71.2)μg/24h. Six cases wihtout hereditary diseases of urinary system were selected as normal control group. SDHB, SDHAF2, SDHC, SDHD, VHL and RET gene mutations were detected in all patients. Immunohistochemical panel has been performed to detect the expression of SDHB, MIB-1, EPAS1, VEGF-1 receptor (VEGF-1R), and chromain A (CgA) in 93 specimens of PHEO/PGL tissue. The positive granular cytoplasm staining >50% was strongly positive (+ + + ), 11% to 50% was moderately positive (+ + ), 1% to 10% was weak positive (+ ) and the negative was compared with the known positive internal reference, that is, there was less than 1% or no stain completely. Results SDHB, SDHAF2, SDHC, SDHD, VHL and RET gene mutations in 27 cases (29.5%). Nine patients with SDHB gene mutation (9.7%). RET proto-oncogene mutations in 8 cases (8.6%). 3 cases had VHL mutation (3.2%). Immunohistochemical staining showed that MIB-1 positive expression was found in 7 of 9 patients with SDHB gene mutation. Six cases in the control group were negative for gene detection and MIB-1, EPAS1, CgA and VEGF-1R immunohistochemical results. EPAS1 showed moderately positive in patients with PHEO/PGL and strong positive in patients with malignant PHEO/PGL. In 9 cases with SDHM mutation, EPAS1 was noticed positive in seven cases, which showed the relationship with CgA, MIB-1 and VEGF-1R. Conclusions The SDHB gene mutation is usually shown as a paraganglioma focus outside the adrenal gland. And 9.8% of the paragangliomas were associated with a mutation of the SDHB gene with an increase in malignant risk. The SDHB mutation caused over-expression of MIB-1 and the positive expression of EPAS1 and VEGF-1R in PHEO/PGL tissues, which was associated with invasion and metastasis of malignant PHEO/PGL. Key words: Pheochromocytoma; Paraganglioma; Succinate dehydrogenase B