Preliminary Investigation On Recurrent Mechanism Of Infantile Hemangioma After Propranolol Treatment

Objective: Infantile hemangioma is the most common benign tumor of infancy. Its rapid growth in the early stage can lead to severe deformity and developmental disorders of organs. Propranolol has been the first choice for severe infantile hemangiomas so far. However, 10% to 30% lesions replased after propranolol was stopped. Undoubtedly, recurrence has become the next hotspot. The mechanism of propranolol for infantile hemangioma and recurrence after termination of treatment has not been completely clarified. This study combined pathological features, hemodynamic changes, differentially expressed mi RNAs with the research of hemangioma stem cells to initially clarify the mechanism of recurrence after termination of propranolol treatment.Methods: From December of 2008 to May of 2014, there were 679 infantile hemangiomas who received propranolol in the outpatient were included in this prospective study. We got two biopsies from two recurrent lesions, and used ultra-high-frequency color Doppler ultrasound to monitor the therapeutic process and hemodynamic changes of 21 recurrent cases. At the cellular level, we explored the mechanism of propranolol and recurrence after termination of propranolol treatment. Lastly, we searched for differentially expressed mi RNAs from serum between 20 non-recurrent cases and 18 recurrent cases.Results: The safety and efficacy rate of oral propranolol for infantile hemangioma in the outpatient were high. There were 92 recurrent cases among 679 patients, and the recurrent rate was 13.5%. There were some fibrofatty infiltration and increased endothelial cell activity in the two recurrent cases, and immunohistochemical staining with CD31 and glut-1 antigens were positive. Their pathological features were similar to proliferative infantile hemangiomas. The lesion shallowed, the vessel density decreased and the resistant index increased during the treatment course. Obvious lesion and vessel signal were seen in recurrent cases.Compared with other cells, hemangioma stem cells were more sensitive to propranolol. Propranolol can inhibit the proliferation of hemangioma stem cells, but it could not induce the apoptosis of hemangioma stem cells. Compared recurrent group with non-recurrent group, 22 differentially expressed mi RNAs were found. Subsequently, 17529 target genes were predicted and seveval signaling pathways were inferred to relate to recurrent mechanism.Conclusion: Although there were some recurrent cases after termination of propranolol treatment, propranolol could be an efficient and safe way for infantile hemangiomas. There were active proliferation of endothelial cells in recurrent lesions, and they may be owing to remained lesions. Hemangioma stem cells may play an important role in the recurrent process. Hemodymic changes probably play a key role in the mechanism of propranolol for infantile hemangioma. There were 22 differentially expressed mi RNAs between recurrent and non-recurrent groups. Further validation is necessary.